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Heteroaryl Benzamide Derivatives for Use as GLK Activators in the
Treatment of Diabetes

Abstract

Compounds of Formula (I):
##STR00001##
wherein: R.sup.1 is hydroxymethyl; R.sup.2 is selected from
--C(O)NR.sup.4R.sup.5, --SO.sub.2NR.sup.4R.sup.5, --S(O).sub.pR.sup.4 and
HET-2; HET-1 is a 5- or 6-membered, optionally substituted C-linked
heteroaryl ring; HET-2 is a 4-, 5- or 6-membered, C- or N-linked
optionally substituted heterocyclyl ring; R.sup.3 is selected from halo,
fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano;
R.sup.4 is selected from for example hydrogen, optionally substituted
(1-4C)alkyl and HET-2; R.sup.5 is hydrogen or (1-4C)alkyl; or R.sup.4 and
R.sup.5 together with the nitrogen atom to which they are attached may
form a heterocyclyl ring system as defined by HET-3; HET-3 is for example
an optionally substituted N-linked, 4, 5 or 6 membered, saturated or
partially unsaturated heterocyclyl ring; p is (independently at each
occurrence) 0, 1 or 2; m is 0 or 1; n is 0, 1 or 2; provided that when m
is 0, then n is 1 or 2;or a salt, pro-drug or solvate thereof, are
described.
Their use as GLK activators, pharmaceutical compositions containing them,
and processes for their preparation are also described.

18. A compound of Formula (I), or a salt, pro-drug, or solvate thereof:
##STR00225## wherein:R.sup.1 is hydroxymethyl;R.sup.2 is selected from
--C(O)NR.sup.4R.sup.5, --SO.sub.2NR.sup.4R.sup.5, and
--S(O).sub.pR.sup.4;HET-1 is a 5- or 6-membered, C-linked heteroaryl ring
containing a nitrogen atom in the 2-position and optionally 1 or 2
further ring heteroatoms independently selected from O, N, and S; which
ring is optionally substituted on an available carbon atom, or on a ring
nitrogen atom provided it is not thereby quaternised, with 1 or 2
substituents independently selected from R.sup.6;R.sup.3 is selected from
halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy, and
cyano;R.sup.4 is selected from hydrogen and (1-4C)alkyl;R.sup.5 is
hydrogen or (1-4C)alkyl;R.sup.6 is independently selected from
(1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl,
(1-4C)alkylS(O).sub.p(1-4C)alkyl, amino(1-4C)alkyl,
(1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl, and
HET-4;HET-4 is a 5- or 6-membered, C- or N-linked unsubstituted
heteroaryl ring containing 1, 2, or 3 ring heteroatoms independently
selected from O, N, and S;p is independently at each occurrence 0, 1, or
2;m is 0 or 1;n is 0, 1, or 2;provided that when m is 0, then n is 1 or
2.

21. A compound of Formula (I), or a salt, pro-drug, or solvate thereof:
##STR00226## wherein:R.sup.1 is hydroxymethyl;R.sup.2 is selected from
--C(O)--HET-3 and --SO.sub.2-HET-3;HET-1 is a 5- or 6-membered, C-linked
heteroaryl ring containing a nitrogen atom in the 2-position and
optionally 1 or 2 further ring heteroatoms independently selected from O,
N, and S; which ring is optionally substituted on an available carbon
atom, or on a ring nitrogen atom provided it is not thereby quaternised,
with 1 or 2 substituents independently selected from R.sup.6;HET-2 is a
4-, 5- or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2,
3, or 4 heteroatoms independently selected from O, N, and S, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)--, and wherein
a sulphur atom in the heterocyclic ring may optionally be oxidised to a
S(O) or S(O).sub.2 group, which ring is optionally substituted on an
available carbon or nitrogen atom by 1 or 2 substituents independently
selected from R.sup.7;R.sup.3 is selected from halo, fluoromethyl,
difluoromethyl, trifluoromethyl, methyl, methoxy, and cyano;R.sup.4 is
selected from hydrogen; (1-4C)alkyl optionally substituted with 1 or 2
substituents independently selected from HET-2, --OR.sup.5,
--SO.sub.2R.sup.5, (3-6C)cycloalkyl (optionally substituted with 1 group
selected from R.sup.7), and --C(O)NR.sup.5R.sup.5; (3-6C)cycloalkyl
(optionally substituted with 1 group selected from R.sup.7); and
HET-2;R.sup.5 is hydrogen or (1-4C)alkyl;or R.sup.4 and R.sup.5 together
with the nitrogen atom to which they are attached may form a heterocyclyl
ring system as defined by HET-3;R.sup.6 is independently selected from
(1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl,
(1-4C)alkylS(O).sub.p(1-4C)alkyl, amino(1-4C)alkyl,
(1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl, and
HET-4;R.sup.7 is selected from --OR.sup.5, (1-4C)alkyl,
--C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5, (1-4C)alkoxy(1-4C)alkyl,
hydroxy(1-4C)alkyl, and --S(O).sub.pR.sup.5;HET-3 is an N-linked, 4-, 5-
or 6-membered, saturated or partially unsaturated heterocyclyl ring,
optionally containing 1 or 2 further heteroatoms (in addition to the
linking N atom) independently selected from O, N, and S, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)-- and wherein a
sulphur atom in the ring may optionally be oxidised to a S(O) or
S(O).sub.2 group; which ring is optionally substituted on an available
carbon or nitrogen atom by 1 or 2 substituents independently selected
from R.sup.8; orHET-3 is an N-linked, 7-membered, saturated or partially
unsaturated heterocyclyl ring, optionally containing 1 further heteroatom
independently selected from O, S, and N, wherein a --CH.sub.2-- group can
optionally be replaced by a --C(O)-- group and wherein a sulphur atom in
the ring may optionally be oxidised to a S(O) or S(O).sub.2 group; which
ring is optionally substituted on an available carbon or nitrogen atom by
1 or 2 substituents independently selected from R.sup.8; orHET-3 is an 6-
to 10-membered bicyclic saturated or partially unsaturated heterocyclyl
ring, optionally containing 1 further nitrogen atom wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)--; which ring
is optionally substituted on an available carbon or nitrogen atom by 1
substituent selected from hydroxy and R.sup.3;R.sup.8 is selected from
--OR.sup.5, (1-4C)alkyl, --C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5,
(1-4C)alkylamino, di(1-4C)alkylamino, HET-3 wherein said ring is
unsubstituted, (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and
--S(O).sub.pR.sup.5;HET-4 is a 5- or 6-membered, C- or N-linked
unsubstituted heteroaryl ring containing 1, 2, or 3 ring heteroatoms
independently selected from O, N, and S;p is independently at each
occurrence 0, 1, or 2;m is 1;n is 0, 1, or 2.

22. A compound of Formula (I) as claimed in claim 21, or a salt, pro-drug,
or solvate thereof, wherein HET-3 is a 4- to 6-membered ring.

24. A compound of Formula (I) as claimed in claim 21, which is selected
from:3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-me-
thylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
and3-{[4-(azetidin-1-ylcarbonyl)-2-chlorophenyl]oxy}-5-{[(1S)-2-hydroxy-1-
-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;or a salt,
pro-drug, or solvate thereof.

25. A compound of Formula (I), or a salt, pro-drug or solvate thereof:
##STR00227## wherein:R.sup.1 is hydroxymethyl;R.sup.2 is selected from
--C(O)NR.sup.41R.sup.51, --SO.sub.2NR.sup.41R.sup.51 and
--S(O).sub.pR.sup.41;HET-1 is a 5- or 6-membered, C-linked heteroaryl
ring containing a nitrogen atom in the 2-position and optionally 1 or 2
further ring heteroatoms independently selected from O, N, and S; which
ring is optionally substituted on an available carbon atom, or on a ring
nitrogen atom provided it is not thereby quaternised, with 1 or 2
substituents independently selected from R.sup.6;HET-2 is a 4-, 5-, or
6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3, or 4
heteroatoms independently selected from O, N, and S, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)--, and wherein
a sulphur atom in the heterocyclic ring may optionally be oxidised to a
S(O) or S(O).sub.2 group, which ring is optionally substituted on an
available carbon or nitrogen atom by 1 or 2 substituents independently
selected from R.sup.7;R.sup.3 is selected from halo, fluoromethyl,
difluoromethyl, trifluoromethyl, methyl, methoxy, and cyano;R.sup.41 is
selected from (1-4C)alkyl substituted with 1 or 2 substituents
independently selected from HET-2, --OR.sup.5, --SO.sub.2R.sup.5,
(3-6C)cycloalkyl (optionally substituted with 1 group selected from
R.sup.7), and --C(O)NR.sup.5R.sup.5; (3-6C)cycloalkyl (optionally
substituted with 1 group selected from R.sup.7); and HET-2;R.sup.51 is
hydrogen or (1-4C)alkyl;R.sup.4 is selected from (1-4C)alkyl optionally
substituted with 1 or 2 substituents independently selected from HET-2,
--OR.sup.5, --SO.sub.2R.sup.5, (3-6C)cycloalkyl (optionally substituted
with 1 group selected from R.sup.7), and --C(O)NR.sup.5R.sup.5;
(3-6C)cycloalkyl (optionally substituted with 1 group selected from
R.sup.7); and HET-2;R.sup.5 is hydrogen or (1-4C)alkyl;or R.sup.4 and
R.sup.5 together with the nitrogen atom to which they are attached may
form a heterocyclyl ring system as defined by HET-3;R.sup.6 is
independently selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl,
(1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O).sub.p(1-4C)alkyl,
amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl,
di(1-4C)alkylamino(1-4C)alkyl, and HET-4;R.sup.7 is selected from
--OR.sup.5, (1-4C)alkyl, --C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5,
(1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and
--S(O).sub.pR.sup.5;HET-3 is an N-linked, 4-, 5-, or 6-membered,
saturated or partially unsaturated heterocyclyl ring, optionally
containing 1 or 2 further heteroatoms independently selected from O, N,
and S, wherein a --CH.sub.2-- group can optionally be replaced by a
--C(O)-- and wherein a sulphur atom in the ring may optionally be
oxidised to a S(O) or S(O).sub.2 group; which ring is optionally
substituted on an available carbon or nitrogen atom by 1 or 2
substituents independently selected from R.sup.8; orHET-3 is an N-linked,
7-membered, saturated or partially unsaturated heterocyclyl ring,
optionally containing 1 further heteroatom independently selected from O,
S, and N, wherein a --CH.sub.2-- group can optionally be replaced by a
--C(O)-- group and wherein a sulphur atom in the ring may optionally be
oxidised to a S(O) or S(O).sub.2 group; which ring is optionally
substituted on an available carbon or nitrogen atom by 1 or 2
substituents independently selected from R.sup.8; orHET-3 is an 6- to
10-membered bicyclic saturated or partially unsaturated heterocyclyl
ring, optionally containing 1 further nitrogen atom wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)--; which ring
is optionally substituted on an available carbon or nitrogen atom by 1
substituent selected from hydroxy and R.sup.3;R.sup.8 is selected from
--OR.sup.5, (1-4C)alkyl, --C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5,
(1-4C)alkylamino, di(1-4C)alkylamino, HET-3 wherein said ring is
unsubstituted, (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and
--S(O).sub.pR.sup.5;HET-4 is a 5- or 6-membered, C- or N-linked
unsubstituted heteroaryl ring containing 1, 2, or 3 ring heteroatoms
independently selected from O, N, and S;p is independently at each
occurrence 0, 1, or 2;m is 1;n is 0, 1, or 2.

27. A compound of Formula (I), or a salt, pro-drug, or solvate thereof:
##STR00228## wherein:R.sup.1 is hydroxymethyl;R.sup.2 is HET-2;HET-1 is a
5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in
the 2-position and optionally 1 or 2 further ring heteroatoms
independently selected from O, N, and S; which ring is optionally
substituted on an available carbon atom, or on a ring nitrogen atom
provided it is not thereby quaternised, with 1 or 2 substituents
independently selected from R.sup.6;HET-2 is a 4-, 5-, or 6-membered, C-
or N-linked heterocyclyl ring containing 1, 2, 3, or 4 heteroatoms
independently selected from O, N, and S, wherein a --CH.sub.2-- group can
optionally be replaced by a --C(O)--, and wherein a sulphur atom in the
heterocyclic ring may optionally be oxidised to an S(O) or S(O).sub.2
group, which ring is optionally substituted on an available carbon or
nitrogen atom by 1 or 2 substituents independently selected from
R.sup.7;R.sup.3 is selected from halo, fluoromethyl, difluoromethyl,
trifluoromethyl, methyl, methoxy, and cyano;R.sup.4 is selected from
hydrogen; (1-4C)alkyl optionally substituted with 1 or 2 substituents
independently selected from HET-2, --OR.sup.5, --SO.sub.2R.sup.5,
(3-6C)cycloalkyl (optionally substituted with 1 group selected from
R.sup.7), and --C(O)NR.sup.5R.sup.5; (3-6C)cycloalkyl (optionally
substituted with 1 group selected from R.sup.7); and HET-2;R.sup.5 is
hydrogen or (1-4C)alkyl;or R.sup.4 and R.sup.5 together with the nitrogen
atom to which they are attached form a heterocyclyl ring system as
defined by HET-3;R.sup.6 is independently selected from (1-4C)alkyl,
halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl,
(1-4C)alkylS(O).sub.p(1-4C)alkyl, amino(1-4C)alkyl,
(1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl, and
HET-4;R.sup.7 is selected from --OR.sup.5, (1-4C)alkyl,
--C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5, (1-4C)alkoxy(1-4C)alkyl,
hydroxy(1-4C)alkyl, and --S(O).sub.pR.sup.5;HET-3 is an N-linked, 4-, 5-,
or 6-membered, saturated or partially unsaturated heterocyclyl ring,
optionally containing 1 or 2 further heteroatoms independently selected
from O, N, and S, wherein a --CH.sub.2-- group can optionally be replaced
by a --C(O)-- and wherein a sulphur atom in the ring may optionally be
oxidised to an S(O) or S(O).sub.2 group; which ring is optionally
substituted on an available carbon or nitrogen atom by 1 or 2
substituents independently selected from R.sup.8; orHET-3 is an N-linked,
7-membered, saturated or partially unsaturated heterocyclyl ring,
optionally containing 1 further heteroatom independently selected from O,
S, and N, wherein a --CH.sub.2-- group can optionally be replaced by a
--C(O)-- group and wherein a sulphur atom in the ring may optionally be
oxidised to an S(O) or S(O).sub.2 group; which ring is optionally
substituted on an available carbon or nitrogen atom by 1 or 2
substituents independently selected from R.sup.8; orHET-3 is an 6- to
10-membered bicyclic saturated or partially unsaturated heterocyclyl
ring, optionally containing 1 further nitrogen atom, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)--; which ring
is optionally substituted on an available carbon or nitrogen atom by 1
substituent selected from hydroxy and R.sup.3;R.sup.8 is selected from
--OR.sup.5, (1-4C)alkyl, --C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5,
(1-4C)alkylamino, di(1-4C)alkylamino, HET-3 wherein said ring is
unsubstituted, (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and
--S(O).sub.pR.sup.5;HET-4 is a 5- or 6-membered, C- or N-linked
unsubstituted heteroaryl ring containing 1, 2, or 3 ring heteroatoms
independently selected from O, N, and S;p is independently at each
occurrence 0, 1, or 2;m is 1;n is 0, 1, or 2.

28. A compound of Formula (I), as claimed in claim 27, which is selected
from:3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4--
(1,2,4-oxadiazol-3-yl)phenoxy]benzamide;
and3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(1-
H-pyrazol-3-yl)phenoxy]benzamide;or a salt, pro-drug, or solvate thereof.

29. A compound of Formula (I) as claimed in claim 18, claim 21, claim 25,
or claim 27 or a salt, pro-drug, or solvate thereof wherein R.sup.1 has
the (S) configuration.

30. A compound of Formula (I) as claimed in claim 18, claim 21, claim 25,
or claim 27 or a salt, pro-drug, or solvate thereof, wherein HET-1 is a
5-membered ring.

31. A pharmaceutical composition comprising a compound as claimed in claim
18, claim 21, claim 25, or claim 27, or a salt, pro-drug, or solvate
thereof, together with a pharmaceutically acceptable diluent or carrier.

32. A method of treating GLK mediated diseases comprising administering an
effective amount of a compound of Formula (I) as claimed in claim 18,
claim 21, claim 25, or claim 27 or a salt, pro-drug, or solvate thereof,
to a mammal in need of such treatment.

34. A process for the preparation of a compound of Formula (I), or a salt,
pro-drug, or solvate thereof as claimed in claim 18, claim 21, claim 25,
or claim 27, comprising:(a) reacting an acid of Formula (III) or
activated derivative thereof with a compound of Formula (IV),
##STR00229## or(b) reacting a compound of Formula (V) with a compound of
Formula (VI), ##STR00230## wherein X.sup.1 is a leaving group and X.sup.2
is a hydroxyl group; or X.sup.1 is a hydroxyl group and X.sup.2 is a
leaving group;orreacting a compound of Formula (V) with the intermediate
ester of Formula (VII), wherein P.sup.1 is a protecting group followed by
ester hydrolysis and amide formation; ##STR00231## or(c) reacting a
compound of Formula (VIII) with a compound of Formula (IX) ##STR00232##
wherein X.sup.3 is a leaving group or an organometallic reagent and
X.sup.4 is a hydroxyl group; orX.sup.3 is a hydroxyl group and X.sup.4 is
a leaving group or an organometallic reagent;orreacting a compound of
Formula (VIII) with the intermediate ester of Formula (X), followed by
ester hydrolysis and amide formation; ##STR00233## or(d) reacting a
compound of Formula (XI) with a compound of Formula (XII), ##STR00234##
wherein X.sup.5 is a leaving group;ore) when R.sup.2 is of the Formula
--C(O)NR.sup.4R.sup.5, reacting a compound of Formula: ##STR00235## with
a compound of the Formula HNR.sup.4R.sup.5;and thereafter, if
necessary:i) converting a compound of Formula (I) into another compound
of Formula (I);ii) removing any protecting groups; and oriii) forming a
salt, pro-drug or solvate.

[0001]This application is a Continuation Application of copending U.S.
patent application Ser. No. 11/628,448, filed Dec. 4, 2006, which is a
U.S. National Phase Application of International Application No.
PCT/GB2005/002166, filed Jun. 1, 2005, which claims the benefit of Great
Britain Patent Application No. 0412602.5, filed Jun. 5, 2004, Great
Britain Patent Application No. 0423041.3, filed Oct. 16, 2004, and Great
Britain Patent Application No. 0502961.6, filed Feb. 12, 2005, all of
which are hereby incorporated by reference in their entirety.

[0002]The present invention relates to a group of benzoyl amino
heterocyclyl compounds which are useful in the treatment or prevention of
a disease or medical condition mediated through glucokinase (GLK or GK),
leading to a decreased glucose threshold for insulin secretion. In
addition the compounds are predicted to lower blood glucose by increasing
hepatic glucose uptake. Such compounds may have utility in the treatment
of Type 2 diabetes and obesity. The invention also relates to
pharmaceutical compositions comprising said compounds and to methods of
treatment of diseases mediated by GLK using said compounds.

[0003]In the pancreatic .beta.-cell and liver parenchymal cells the main
plasma membrane glucose transporter is GLUT2. Under physiological glucose
concentrations the rate at which GLUT2 transports glucose across the
membrane is not rate limiting to the overall rate of glucose uptake in
these cells. The rate of glucose uptake is limited by the rate of
phosphorylation of glucose to glucose-6-phosphate (G-6-P) which is
catalysed by glucokinase (GLK) [1]. GLK has a high (6-10 mM) Km for
glucose and is not inhibited by physiological concentrations of G-6-P
[1]. GLK expression is limited to a few tissues and cell types, most
notably pancreatic .beta.-cells and liver cells (hepatocytes) [1]. In
these cells GLK activity is rate limiting for glucose utilisation and
therefore regulates the extent of glucose induced insulin secretion and
hepatic glycogen synthesis. These processes are critical in the
maintenance of whole body glucose homeostasis and both are dysfunctional
in diabetes [2].

[0004]In one sub-type of diabetes, Maturity-Onset Diabetes of the Young
Type 2 (MODY-2), the diabetes is caused by GLK loss of function mutations
[3,4]. Hyperglycaemia in MODY-2 patients results from defective glucose
utilisation in both the pancreas and liver [5]. Defective glucose
utilisation in the pancreas of MODY-2 patients results in a raised
threshold for glucose stimulated insulin secretion. Conversely, rare
activating mutations of GLK reduce this threshold resulting in familial
hyperinsulinism [6, 6a, 7]. In addition to the reduced GLK activity
observed in MODY-2 diabetics, hepatic glucokinase activity is also
decreased in type 2 diabetics [8]. Importantly, global or liver selective
overexpression of GLK prevents or reverses the development of the
diabetic phenotype in both dietary and genetic models of the disease
[9-12]. Moreover, acute treatment of type 2 diabetics with fructose
improves glucose tolerance through stimulation of hepatic glucose
utilisation [1,3]. This effect is believed to be mediated through a
fructose induced increase in cytosolic GLK activity in the hepatocyte by
the mechanism described below [13].

[0005]Hepatic GLK activity is inhibited through association with GLK
regulatory protein (GLKRP). The GLK/GLKRP complex is stabilised by
fructose-6-phosphate (F6P) binding to the GLKRP and destabilised by
displacement of this sugar phosphate by fructose-1-phosphate (F1P). F1P
is generated by fructokinase mediated phosphorylation of dietary
fructose. Consequently, GLK/GLKRP complex integrity and hepatic CGLK
activity is regulated in a nutritionally dependent manner as F6P is
dominant in the post-absorptive state whereas F1P predominates in the
post-prandial state. In contrast to the hepatocyte, the pancreatic
.beta.-cell expresses GLK in the absence of GLKRP. Therefore, .beta.-cell
GLK activity is regulated extensively by the availability of its
substrate, glucose. Small molecules may activate GLK either directly or
through destabilising the GLK/GLKP complex. The former class of compounds
are predicted to stimulate glucose utilisation in both the liver and the
pancreas whereas the latter are predicted to act selectively in the
liver. However, compounds with either profile are predicted to be of
therapeutic benefit in treating Type 2 diabetes as this disease is
characterised by defective glucose utilisation in both tissues.

[0006]GLK, GLKRP and the K.sub.ATP channel are expressed in neurones of
the hypothalamus, a region of the brain that is important in the
regulation of energy balance and the control of food intake [14-18].
These neurones have been shown to express orectic and anorectic
neuropeptides [15, 19, 20] and have been assumed to be the
glucose-sensing neurones within the hypothalamus that are either
inhibited or excited by changes in ambient glucose concentrations [17,
19, 21, 22]. The ability of these neurones to sense changes in glucose
levels is defective in a variety of genetic and experimentally induced
models of obesity [23-28]. Intracerebroventricular (icv) infusion of
glucose analogues, that are competitive inhibitors of glucokinase,
stimulate food intake in lean rats [29, 30]. In contrast, icv infusion of
glucose suppresses feeding [31]. Thus, small molecule activators of GLK
may decrease food intake and weight gain through central effects on GLK.
Therefore, GLK activators may be of therapeutic use in treating eating
disorders, including obesity, in addition to diabetes. The hypothalamic
effects will be additive or synergistic to the effects of the same
compounds acting in the liver and/or pancreas in normalising glucose
homeostasis, for the treatment of Type 2 diabetes. Thus the GLK/GLKRP
system can be described as a potential "Diabesity" target (of benefit in
both Diabetes and Obesity).

[0007]GLK is also expressed in specific entero-endocrine cells where it is
believed to control the glucose sensitive secretion of the incretin
peptides GIP (glucose-dependent insulinotropic polypeptide) and GLP-1
(Glucagon-Like Peptide-1) from gut K-cells and L-cells respectively (32,
33, 34). Therefore, small molecule activators of GLK may have additional
beneficial effects on insulin secretion, b-cell function and survival and
body weight as a consequence of stimulating GIP and GLP-1 secretion from
these entero-endocrine cells.

[0008]In WO00/58293 and WO01/44216 (Roche), a series of benzylcarbamoyl
compounds are described as glucokinase activators. The mechanism by which
such compounds activate GLK is assessed by measuring the direct effect of
such compounds in an assay in which GLK activity is linked to NADH
production, which in turn is measured optically--see details of the in
vitro assay described hereinafter. Compounds of the present invention may
activate GLK directly or may activate GLK by inhibiting the interaction
of GLKRP with GLK.

wherein R.sup.3 is a substituted heterocycle other than a carboxylic acid
substituted pyridyl.

[0012]International application WO2004/076420 (Banyu) describes compounds
which are generally a subset of those described in WO03/01574, wherein
for example R.sup.1 is an (substituted) alkyl ether and R.sup.2 is
(substituted) phenoxy.

[0013]We have surprisingly found a small group of compounds, generally a
selected subgroup of those described in WO 03/015774, which have
generally superior potency for the GLK enzyme, and more advantageous
physical properties, including, for example, higher aqueous solubility,
higher permeability, and/or lower plasma protein binding. Consequently,
such compounds having a balance of these properties would be expected to
display higher plasma free drug levels and superior in vivo efficacy
after oral dosing as determined, for example, by activity in Oral Glucose
Tolerance Tests (OGTTs). Therefore this group of compounds would be
expected to provide superior oral exposure at a lower dose and thereby be
particularly suitable for use in the treatment or prevention of a disease
or medical condition mediated through GLK.

[0014]Thus, according to the first aspect of the invention there is
provided a compound of Formula (I):

##STR00003##

wherein:R.sup.1 is hydroxymethyl;R.sup.2 is selected from
--C(O)NR.sup.4R.sup.5, --SO.sub.2NR.sup.4R.sup.5, --S(O).sub.pR.sup.4 and
HET-2;HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a
nitrogen atom in the 2-position and optionally 1 or 2 further ring
heteroatoms independently selected from O, N and S; which ring is
optionally substituted on an available carbon atom, or on a ring nitrogen
atom provided it is not thereby quaternised, with 1 or 2 substituents
independently selected from R.sup.6;HET-2 is a 4-, 5- or 6-membered, C-
or N-linked heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms
independently selected from O, N and S, wherein a --CH.sub.2-- group can
optionally be replaced by a --C(O)--, and wherein a sulphur atom in the
heterocyclic ring may optionally be oxidised to a S(O) or S(O).sub.2
group, which ring is optionally substituted on an available carbon or
nitrogen atom by 1 or 2 substituents independently selected from
R.sup.7;R.sup.3 is selected from halo, fluoromethyl, difluoromethyl,
trifluoromethyl, methyl, methoxy and cyano;R.sup.4 is selected from
hydrogen, (1-4C)alkyl [optionally substituted by 1 or 2 substituents
independently selected from HET-2, --OR.sup.5, --SO.sub.2R.sup.5],
(3-6C)cycloalkyl (optionally substituted with group selected from
R.sup.7) and --C(O)NR.sup.5R.sup.5], (3-6C)cycloalkyl (optionally
substituted with 1 group selected from R.sup.7) and HET-2;R.sup.5 is
hydrogen or (1-4C)alkyl;or R.sup.4 and R.sup.5 together with the nitrogen
atom to which they are attached may form a heterocyclyl ring system as
defined by HET-3;R.sup.6 is independently selected from (1-4C)alkyl,
halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl,
(1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,
(1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl and
HET-4;R.sup.7 is selected from --OR.sup.5, (1-4C)alkyl,
--C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5, (1-4C)alkoxy(1-4C)alkyl,
hydroxy(1-4C)alkyl and --S(O)pR.sup.5;HET-3 is an N-linked, 4 to 6
membered, saturated or partially unsaturated heterocyclyl ring,
optionally containing 1 or 2 further heteroatoms (in addition to the
linking N atom) independently selected from O, N and S, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)-- and wherein a
sulphur atom in the ring may optionally be oxidised to a S(O) or
S(O).sub.2 group; which ring is optionally substituted on an available
carbon or nitrogen atom by 1 or 2 substituents independently selected
from R.sup.8; orHET-3 is an N-linked, 7 membered, saturated or partially
unsaturated heterocyclyl ring, optionally containing 1 further heteroatom
(in addition to the linking N atom) independently selected from O, S and
N, wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)--
group and wherein a sulphur atom in the ring may optionally be oxidised
to a S(O) or S(O).sub.2 group; which ring is optionally substituted on an
available carbon or nitrogen atom by 1 or 2 substituents independently
selected from R.sup.8; orHET-3 is an 6-10 membered bicyclic saturated or
partially unsaturated heterocyclyl ring, optionally containing 1 further
nitrogen atom (in addition to the linking N atom), wherein a --CH.sub.2--
group can optionally be replaced by a --C(O)--; which ring is optionally
substituted on an available carbon or nitrogen atom by 1 substituent
selected from hydroxy and R.sup.3;R.sup.8 is selected from --OR.sup.5,
(1-4C)alkyl, --C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5, (1-4C)alkylamino,
di(1-4C)alkylamino, HET-3 (wherein said ring is unsubstituted),
(1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl and --S(O)pR.sup.5;HET-4 is a
5- or 6-membered, C- or N-linked unsubstituted heteroaryl ring containing
1, 2 or 3 ring heteroatoms independently selected from O, N and S;p is
(independently at each occurrence) 0, 1 or 2;m is 0 or 1;n is 0, 1 or
2;provided that when m is 0, then n is 1 or 2;or a salt, pro-drug or
solvate thereof.

[0015]In a further aspect of the invention there is provided a compound of
formula (I), or a salt, pro-drug or solvate thereof as hereinbefore
defined, with the proviso that compounds exemplified in WO2004/076420,
which would otherwise fall within the scope of this invention, are
excluded.

[0016]In a further aspect of the invention there is provided a compound of
formula (I), or a salt, pro-drug or solvate thereof as hereinbefore
defined, wherein:

R.sup.1 is hydroxymethyl;R.sup.2 is selected from --C(O)NR.sup.4R.sup.5,
--SO.sub.2NR.sup.4R.sup.5, --S(O).sub.pR.sup.4 and HET-2;HET-1 is a 5- or
6-membered, C-linked heteroaryl ring containing a nitrogen atom in the
2-position and optionally 1 or 2 further ring heteroatoms independently
selected from O, N and S; which ring is optionally substituted on an
available carbon atom, or on a ring nitrogen atom provided it is not
thereby quaternised, with 1 or 2 substituents independently selected from
R.sup.6;HET-2 is a 4-, 5- or 6-membered, C- or N-linked heterocyclyl ring
containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and
S, wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)--,
and wherein a sulphur atom in the heterocyclic ring may optionally be
oxidised to a S(O) or S(O).sub.2 group, which ring is optionally
substituted on an available carbon or nitrogen atom by 1 or 2
substituents independently selected from R.sup.7;R.sup.3 is selected from
halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and
cyano;R.sup.4 is selected from hydrogen, (1-4C)alkyl [optionally
substituted by 1 or 2 substituents independently selected from HET-2,
--OR.sup.5, --SO.sub.2R.sup.5, (3-6C)cycloalkyl (optionally substituted
with 1 group selected from R.sup.7) and --C(O)NR.sup.5R.sup.5] and
HET-2;R.sup.5 is hydrogen or (1-4C)alkyl.or R.sup.4 and R.sup.5 together
with the nitrogen atom to which they are attached may form a heterocyclyl
ring system as defined by HET-3;R.sup.6 is independently selected from
(1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl,
(1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,
(1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl and
HET-4;R.sup.7 is selected from --OR.sup.5, (1-4C)alkyl,
--C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5, (1-4C)alkoxyl(1-4C)alkyl,
hydroxy(1-4C)alkyl and S(O)pR.sup.5;HET-3 is an N-linked, 4 to 6
membered, saturated or partially unsaturated heterocyclyl ring,
optionally containing 1 or 2 further heteroatoms (in addition to the
linking N atom) independently selected from O, N and S, wherein a
--CH.sub.2-- group can optionally be rep laced by a --C(O)-- and wherein
a sulphur atom in the ring may optionally be oxidised to a S(O) or
S(O).sub.2 group; which ring is optionally substituted on an available
carbon or nitrogen atom by 1 or 2 substituents independently selected
from R.sup.8; orHET-3 is an N-linked, 7 membered, saturated or partially
unsaturated heterocyclyl ring, optionally containing 1 further heteroatom
(in addition to the linking N atom) independently selected from O, S and
N, wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)--
group and wherein a sulphur atom in the ring may optionally be oxidised
to a S(O) or S(O).sub.2 group; which ring is optionally substituted on an
available carbon or nitrogen atom by 1 or 2 substituents independently
selected from R.sup.8; orHET-3 is an 6-10 membered bicyclic saturated or
partially unsaturated heterocyclyl ring, optionally containing 1 further
nitrogen atom (in addition to the linking N atom), wherein a --CH.sub.2--
group can optionally be replaced by a --C(O)--; which ring is optionally
substituted on an available carbon or nitrogen atom by 1 substituent
selected from R.sup.3;R.sup.8 is selected from --OR.sup.3, (1-4C)alkyl,
--C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5, (1-4C)alkylamino,
di(1-4C)alkylamino, HET-3 (wherein said ring is unsubstituted),
(1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl and S(O)pR.sup.5:HET-4 is a
5- or 6-membered, C- or N-linked unsubstituted heteroaryl ring containing
1, 2 or 3 ring heteroatoms independently selected from O, N and S;p is
(independently at each occurrence) 0, 1 or 2;m is 0 or 1;n is 0, 1 or
2;provided that when m is 0, then n is 1 or 2;or a salt, pro-drug or
solvate thereof.

[0017]In another aspect of the invention, there is provided a compound of
the formula (I) as hereinbefore defined, wherein

R.sup.1 is hydroxymethyl;R.sup.2 is selected from --C(O)-HET-3 and
--SO.sub.2-HET-3;HET-1 is a 5- or 6-membered, C-linked heteroaryl ring
containing a nitrogen atom in the 2-position and optionally 1 or 2
further ring heteroatoms independently selected from O, N and S; which
ring is optionally substituted on an available carbon atom, or on a ring
nitrogen atom provided it is not thereby quaternised, with 1 or 2
substituents independently selected from R.sup.6;HET-2 is a 4-, 5- or
6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3 or 4
heteroatoms independently selected from O, N and S, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)--, and wherein
a sulphur atom in the heterocyclic ring may optionally be oxidised to a
S(O) or S(O).sub.2 group, which ring is optionally substituted on an
available carbon or nitrogen atom by 1 or 2 substituents independently
selected from R.sup.7;R.sup.3 is selected from halo, fluoromethyl,
difluoromethyl, trifluoromethyl, methyl, methoxy and cyano;R.sup.4 is
selected from hydrogen, (1-4C)alkyl [optionally substituted by 1 or 2
substituents independently selected from HET-2, --OR.sup.5,
--SO.sub.2R.sup.5, (3-6C)cycloalkyl (optionally substituted with 1 group
selected from R.sup.7) and --C(O)NR.sup.5R.sup.5], (3-6C)cycloalkyl
(optionally substituted with 1 group selected from R.sup.7) and
HET-2;R.sup.5 is hydrogen or (1-4C)alkyl; orR.sup.4 and R.sup.5 together
with the nitrogen atom to which they are attached may form a heterocyclyl
ring system as defined by HET-3;R.sup.6 is independently selected from
(1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl,
(1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,
(1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl and
HET-4;R.sup.7 is selected from --OR.sup.5, (1-4C)alkyl,
--C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5, (1-4C)alkoxy(1-4C)alkyl,
hydroxy(1-4C)alkyl and --S(O)pR.sup.5;HET-3 is an N-linked, 4, 5 or 6
membered, saturated or partially unsaturated heterocyclyl ring,
optionally containing 1 or 2 further heteroatoms (in addition to the
linking N atom) independently selected from O, N and S, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)-- and wherein a
sulphur atom in the ring may optionally be oxidised to a S(O) or
S(O).sub.2 group; which ring is optionally substituted on an available
carbon or nitrogen atom by 1 or 2 substituents independently selected
from R.sup.8; orHET-3 is an N-linked, 7 membered, saturated or partially
unsaturated heterocyclyl ring, optionally containing 1 fisher heteroatom
(in addition to the linking N atom) independently selected from O, S and
N, wherein a --CH.sub.2-- group can optionally be replaced by a
--C(O)--group and wherein a sulphur atom in the ring may optionally be
oxidised to a S(O) or S(O).sub.2 group; which ring is optionally
substituted on an available carbon or nitrogen atom by 1 or 2
substituents independently selected from R.sup.8; orHET-3 is an 6-10
membered bicyclic saturated or partially unsaturated heterocyclyl ring,
optionally containing 1 further nitrogen atom (in addition to the linking
N atom) wherein a --CH.sub.2-- group can optionally be replaced by a
--C(O)--; which ring is optionally substituted on an available carbon or
nitrogen atom by 1 substituent selected from hydroxy and R.sup.3;R.sup.8
is selected from --OR.sup.5, (1-4C)alkyl, --C(O)(1-4C)alkyl,
--C(O)NR.sup.4R.sup.5, (1-4C)alkylamino, di(1-4C)alkylamino, HET-3
(wherein said ring is unsubstituted), (1-4C)alkoxy(1-4C)alkyl,
hydroxy(1-4C)alkyl and --S(O)pR.sup.5;HET-4 is a 5- or 6-membered, C- or
N-linked unsubstituted heteroaryl ring containing 1, 2 or 3 ring
heteroatoms independently selected from O, N and S;p is (independently at
each occurrence) 0, 1 or 2;m is 0 or 1;n is 0, 1 or 2;provided that when
m is 0, then n is 1 or 2;or a salt, pro-drug or solvate thereof.

[0018]In a further aspect of the invention there is provided a compound of
the formula (I), as hereinbefore defined or a salt, pro-drug or solvate
thereof, wherein:

HET-3 is an N-linked, 4 to 6 membered, saturated or partially unsaturated
heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in
addition to the linking N atom) independently selected from O, N and S,
wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)-- and
wherein a sulphur atom in the ring may optionally be oxidised to a S(O)
or S(O).sub.2 group; which ring is optionally substituted on an available
carbon or nitrogen atom by 1 or 2 substituents independently selected
from R.sup.8.

[0019]In another aspect of the invention, there is provided a compounds of
the formula (I) as hereinbefore defined, wherein

R.sup.1 is hydroxymethyl;R.sup.2 is selected from --(CO)NR.sup.41R.sup.51,
--SO.sub.2NR.sup.41R.sup.51 and --S(O).sub.pR.sup.41;HET-1 is a 5- or
6-membered, C-linked heteroaryl ring containing a nitrogen atom in the
2-position and optionally 1 or 2 further ring heteroatoms independently
selected from O, N and S; which ring is optionally substituted on an
available carbon atom, or on a ring nitrogen atom provided it is not
thereby quaternised, with 1 or 2 substituents independently selected from
R.sup.6;HET-2 is a 4-, 5- or 6-membered, C- or N-linked heterocyclyl ring
containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and
S, wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)--,
and wherein a sulphur atom in the heterocyclic ring may optionally be
oxidised to a S(O) or S(O).sub.2 group, which ring is optionally
substituted on an available carbon or nitrogen atom by 1 or 2
substituents independently selected from R.sup.7;R.sup.3 is selected from
halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and
cyano;R.sup.41 is selected from (1-4C)alkyl [substituted by 1 or 2
substituents independently selected from HET-2, --OR.sup.5,
--SO.sub.2R.sup.5, (3-6C)cycloalkyl (optionally substituted with 1 group
selected from R.sup.7) and --C(O)NR.sup.5R.sup.5], (3-6C)cycloalkyl
(optionally substituted with 1 group selected from R.sup.7) and
HET-2;R.sup.51 is hydrogen or (1-4C)alkyl;R.sup.4 is selected from
(1-4C)alkyl [optionally substituted by 1 or 2 substituents independently
selected from HET-2, --OR.sup.5, --SO.sub.2R.sup.5, (3-6C)cycloalkyl
(optionally substituted with 1 group selected from R.sup.7) and
--C(O)NR.sup.5R.sup.5], (3-6C)cycloalkyl (optionally substituted with 1
group selected from R.sup.7) and HET-2;R.sup.5 is hydrogen or
(1-4C)alkyl;or R.sup.4 and R.sup.5 together with the nitrogen atom to
which they are attached may form a heterocyclyl ring, system as defined
by HET-3;R.sup.6 is independently selected from (1-4C)alkyl, halo,
hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl,
amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl,
di(1-4C)alkylamino(1-4C)alkyl and HET-4;R.sup.7 is selected from
--OR.sup.5, (1-4C)alkyl, --C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5,
(1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl and --S(O)pR.sup.5;HET-3 is
an N-linked, 4, 5 or 6 membered, saturated or partially unsaturated
heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in
addition to the linking N atom) independently selected from O, N and S,
wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)-- and
wherein a sulphur atom in the ring may optionally be oxidised to a S(O)
or S(O).sub.2 group; which ring is optionally substituted on an available
carbon or nitrogen atom by 1 or 2 substituents independently selected
from R.sup.8; orHET-3 is an N-linked, 7 membered, saturated or partially
unsaturated heterocyclyl ring, optionally containing 1 further heteroatom
(in addition to the linking N atom) independently selected from O, S and
N, wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)--
group and wherein a sulphur atom in the ring may optionally be oxidised
to a S(O) or S(O).sub.2 group; which ring is optionally substituted on an
available carbon or nitrogen atom by 1 or 2 substituents independently
selected from R.sup.8; orHET-3 is an 6-10 membered bicyclic saturated or
partially unsaturated heterocyclyl ring, optionally containing 1 further
nitrogen atom (in addition to the linking N atom) wherein a --CH.sub.2--
group can optionally be replaced by a --C(O)--; which ring is optionally
substituted on an available carbon or nitrogen atom by 1 substituent
selected from hydroxy and R.sup.3;R.sup.8 is selected from --OR.sup.5,
(1-4C)alkyl, --C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5, (1-4C)alkylamino,
di(1-4C)alkylamino, HET-3 (wherein said ring is unsubstituted),
(1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl and --S(O)pR.sup.5;HET-4 is a
5- or 6-membered, C- or N-linked unsubstituted heteroaryl ring containing
1, 2 or 3 ring heteroatoms independently selected from O, N and S;p is
(independently at each occurrence) 0, 1 or 2;m is 0 or 1;n is 0, 1 or
2;provided that when m is 0, then n is 1 or 2;or a salt, pro-drug or
solvate thereof.

[0020]In a further aspect of the invention there is provided a compound of
the formula (I) as hereinbefore defined, or a salt, pro-drug or solvate
thereof, wherein:

R.sup.4 is selected from hydrogen, (1-4C)alkyl [optionally substituted by
1 or 2 substituents independently selected from HET-2, --OR.sup.5,
--SO.sub.2R.sup.5, (3-6C)cycloalkyl (optionally substituted with 1 group
selected from R.sup.7) and --C(O)NR.sup.5R.sup.5], and HET-2.HET-3 as an
6-10 membered bicyclic saturated or partially unsaturated heterocyclyl
ring optionally containing 1 further nitrogen atom (in addition to the
linking N atom) wherein a --CH.sub.2-- group can optionally be replaced
by a --C(O)--, is optionally substituted on an available carbon or
nitrogen atom by 1 substituent selected from R.sup.3.

[0021]In another aspect of the invention, there is provided a compound of
the formula (I) as hereinbefore defined, wherein

R.sup.1 is hydroxymethyl;

R.sup.2 is HET-2:

[0022]HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a
nitrogen atom in the 2-position and optionally 1 or 2 further ring
heteroatoms independently selected from O, N and S; which ring is
optionally substituted on an available carbon atom, or on a ring nitrogen
atom provided it is not thereby quaternised, with 1 or 2 substituents
independently selected from R.sup.6;HET-2 is a 4-, 5- or 6-membered, C-
or N-linked heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms
independently selected from O, N and S, wherein a --CH.sub.2-- group can
optionally be replaced by a --C(O)--, and wherein a sulphur atom in the
heterocyclic ring may optionally be oxidised to a S(O) or S(O).sub.2
group, which ring is optionally substituted on an available carbon or
nitrogen atom by 1 or 2 substituents independently selected from
R.sup.7;R.sup.3 is selected from halo, fluoromethyl, difluoromethyl,
trifluoromethyl, methyl, methoxy and cyano;R.sup.4 is selected from
hydrogen, (1-4C)alkyl [optionally substituted by 1 or 2 substituents
independently selected from HET-2, --OR.sup.5, --SO.sub.2R.sup.5,
(3-6C)cycloalkyl (optionally substituted with 1 group selected from
R.sup.7) and --C(O)NR.sup.5R.sup.5], (3-6C)cycloalkyl (optionally
substituted with 1 group selected from R.sup.7) and HET-2;R.sup.5 is
hydrogen or (1-4C)alkyl;or R.sup.4 and R.sup.5 together with the nitrogen
atom to which they are attached may form a heterocyclyl ring system as
defined by HET-3;R.sup.6 is independently selected from (1-4C)alkyl,
halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl,
(1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,
(1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl and
HET-4;R.sup.7 is selected from --OR.sup.5, (1-4C)alkyl,
--C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5, (1-4C)alkoxy(1-4C)alkyl,
hydroxy(1-4C)alkyl and --S(O)pR.sup.5;HET-3 is an N-linked, 4, 5 or 6
membered, saturated or partially unsaturated heterocyclyl ring,
optionally containing 1 or 2 further heteroatoms (in addition to the
linking N atom) independently selected from O, N and S, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)-- and wherein a
sulphur atom in the ring may optionally be oxidised to a S(O) or
S(O).sub.2 group; which ring is optionally substituted on an available
carbon or nitrogen atom by 1 or 2 substituents independently selected
from R.sup.8; orHET-3 is an N-linked, 7 membered, saturated or partially
unsaturated heterocyclyl ring, optionally containing 1 further heteroatom
(in addition to the linking N atom) independently selected from O, S and
N, wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)--
group and wherein a sulphur atom in the ring may optionally be oxidised
to a S(O) or S(O).sub.2 group; which ring is optionally substituted on an
available carbon or nitrogen atom by 1 or 2 substituents independently
selected from R.sup.8; orHET-3 is an 6-10 membered bicyclic saturated or
partially unsaturated heterocyclyl ring, optionally containing 1 further
nitrogen atom (in addition to the linking N atom) wherein a --CH.sub.2--
group can optionally be replaced by a --C(O)--; which ring is optionally
substituted on an available carbon or nitrogen atom by 1 substituent
selected from hydroxy and R.sup.3;R.sup.8 is selected from --OR.sup.5,
(1-4C)alkyl, --C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5, (1-4C)alkylamino,
di(1-4C)alkylamino, HET-3 (wherein said ring is unsubstituted),
(1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl and --S(O)pR.sup.5;HET-4 is a
5- or 6-membered, C- or N-linked unsubstituted heteroaryl ring containing
1, 2 or 3 ring heteroatoms independently selected from O, N and S;p is
(independently at each occurrence) 0, 1 or 2;m is 0 or 1;n is 0, 1 or
2;provided that when m is 0, then n is 1 or 2;or a salt, pro-drug or
solvate thereof.

[0023]It will be understood that when R.sup.4 is --C(O)NR.sup.5R.sup.5,
each R.sup.5 is independently selected from hydrogen and (1-4C)alkyl, and
therefore this definition of R.sup.4 includes (but is not limited to)
--CONH.sub.2, --CONHMe, --CONMe.sub.2 and --CONMeEt.

[0024]It will be understood that where a compound of the formula (I)
contains more than one HET-2 ring, they may be the same or different.

[0025]It will be understood that where a compound of the formula (I)
contains more than one group R.sup.4, they may be the same or different.

[0026]It will be understood that where a compound of the formula (I)
contains more than one group R.sup.5, they may be the same or different.

[0027]It will be understood that where a compound of the formula (I)
contains more than one group R.sup.8, they may be the same or different.

[0028]A similar convention applies for all other groups and substituents
on a compound of formula (I) as hereinbefore defined.

[0029]Compounds of Formula (I) may form salts which are within the ambit
of the invention. Pharmaceutically acceptable salts are preferred
although other salts may be useful in, for example, isolating or
purifying compounds.

[0030]In another aspect, the invention relates to compounds of formula (I)
as hereinabove defined or to a pharmaceutically acceptable salt.

[0031]In another aspect, the invention relates to compounds of formula (I)
as hereinabove defined or to a pro-drug thereof. Suitable examples of
pro-drugs of compounds of formula (I) are in-vivo hydrolysable esters of
compounds of formula (I). Therefore in another aspect, the invention
relates to compounds of formula (I) as hereinabove defined or to an
in-vivo hydrolysable ester thereof.

[0032]In this specification the generic term "alkyl" includes both
straight-chain and branched-chain alkyl groups. However references to
individual alkyl groups such as "propyl" are specific for the straight
chain version only and references to individual branched-chain alkyl
groups such as t-butyl are specific for the branched chain version only.
For example, "(1-4C)alkyl" includes methyl, ethyl, propyl, isopropyl and
t-butyl. An analogous convention applies to other generic terms.

[0033]For the avoidance of doubt, reference to the group HET-1 containing
a nitrogen in the 2-position, is intended to refer to the 2-position
relative to the amide nitrogen atom to which the group is attached. For
example, the following structures are encompassed (but not limited to):

[0039]A suitable example of HET-3 as a 7-membered saturated or partially
unsaturated heterocyclic ring is homopiperazinyl, homo-morpholino,
homo-thiomorpholino (and versions thereof wherein the sulfur is oxidised
to an SO or S(O).sub.2 group) and homo-piperidinyl.

[0040]Suitable examples of HET-3 as an 6-10 membered bicyclic heterocyclic
ring are bicyclic saturated or partially unsaturated heterocyclyl ring
such as those illustrated by the structures shown below (wherein the
dotted line indicates the point of attachment to the rest of the
molecule):

[0044]It will be appreciated that, where definitions of heterocyclyl
groups HET-1 to HET-4 encompass heteroaryl or heterocyclyl rings which
may be substituted on nitrogen, such substitution may not result in
charged quaternary nitrogen atoms or unstable structures (such as N-halo
compounds). It will be appreciated that the definitions of HET-1 to HET-4
are not intended to include any O--O, O--S or S--S bonds. It will be
appreciated that the definitions of HET-1 to HET-4 are not intended to
include unstable structures.

[0046]It is to be understood that, insofar as certain of the compounds of
Formula (I) defined above may exist in optically active or racemic forms
by virtue of one or more asymmetric carbon atoms, the invention includes
in its definition any such optically active or racemic form which
possesses the property of stimulating GLK directly or inhibiting the
GLK/GLKRP interaction. The synthesis of optically active forms may be
carried out by standard techniques of organic chemistry well known in the
art, for example by synthesis from optically active starting materials or
by resolution of a racemic form. It is also to be understood that certain
compounds may exist in tautomeric forms and that the invention also
relates to any and all tautomeric forms of the compounds of the invention
which activate GLK.

[0047]In one embodiment of the invention are provided compounds of formula
(I), in an alternative embodiment are provided
pharmaceutically-acceptable salts of compounds of formula (I), in a
further alternative embodiment are provided in-vivo hydrolysable esters
of compounds of formula (I), and in a further alternative embodiment are
provided pharmaceutically-acceptable salts of in-vivo hydrolysable esters
of compounds of formula (I).

[0048]Preferred values of each variable group are as follows. Such values
may be used where appropriate with any of the values, definitions,
claims, aspects or embodiments defined hereinbefore or hereinafter. In
particular, each may be used as an individual limitation on the broadest
definition of formula (I). Further, each of the following values may be
used in combination with one or more of the other following values to
limit the broadest definition of formula (I).

(1) R.sup.1 is hydroxymethyl and the configuration is preferably (S), that
is:

##STR00009##

(2) R.sup.2 is --C(O)NR.sup.4R.sup.5

(3) R.sup.2 is --SO.sub.2NR.sup.4R.sup.5

(4) R.sup.2 is --S(O).sub.pR.sup.4

(5) R.sup.2 is HET-2

[0049](6) m is 1 and preferably R.sup.2 is in the para position relative
to the ether linkage(7) m is 1 and n is 0 or 1(8) m is 1 and n is 0(9) m
is 1, n is 0 and R.sup.2 is in the para position relative to the ether
linkage(10) m is 1, n is 1, R.sup.2 is in the para position relative to
the ether linkage, R.sup.3 is in the ortho position relative to the ether
linkage(11) m is 1, n is 1, R.sup.2 is in the para position relative to
the ether linkage, R.sup.3 is in the meta position relative to the ether
linkage(12) n is 0(13) n is 1(14) n is 2(15) n is 2 and both R.sup.3 are
halo(16) n is 2 and each R.sup.3 is independently halo or methoxy(17) m
is 1, n is 2 and R.sup.2 is in the para position relative to the ether
linkage(18) m is 1, n is 2, R.sup.2 is in the para position relative to
the ether linkage and each R.sup.3 is in an ortho position relative to
the ether linkage(19) m is 1, n is 2, both R.sup.3 are halo, R.sup.2 is
in the para position relative to the ether linkage and each R.sup.3 is in
an ortho position relative to the ether linkage(20) m is 1, n is 2, both
R.sup.3 are halo, R.sup.12 is in the para position relative to the ether
linkage and one R.sup.3 is in an ortho position relative to the ether
linkage and the other R.sup.3 is in a meta position relative to the ether
linkage(21) R.sup.3 is fluoromethyl or difluoromethyl(22) R.sup.3 is halo
or trifluoromethyl(23) R.sup.3 is halo(24) R.sup.3 is chloro or
fluoro(25) R.sup.3 is fluoro(26) R.sup.3 is methoxy(27) n is 2 and both
R.sup.3 are fluoro(28) n is 2 and one R.sup.3 is fluoro and the other is
chloro(29) n is 2, both R.sup.3 are fluoro and are in the 3- and
5-positions (meta-positions) relative to the ether linkage(30) m is 1, n
is 2, R.sup.2 is in the para position relative to the ether linkage, both
R.sup.3 are fluoro and are in the 3- and 5-positions relative to the
ether linkage(31) p is 0(32) p is 1(33) p is 2(34) HET-1 is a 5-membered
heteroaryl ring(35) HET-1 is a 6-membered heteroaryl ring(36) HET-1 is
substituted with 1 or 2 substituents independently selected from R.sup.6
(37) HET-1 is substituted with 1 substituent selected from R.sup.6 (38)
HET-1 is unsubstituted(39) HET-1 is selected from thiazolyl,
isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl,
imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, and
triazolyl(40) RET-t is selected from thiazolyl, isothiazolyl,
thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and
oxadiazolyl(41) HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl
and pyrimidinyl(42) HET-1 is selected from thiazolyl, pyrazolyl and
oxazolyl(43) HET-1 is selected from thiadiazolyl and oxadiazolyl(44)
HET-1 is selected from 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl(45) HET-1
is selected from 1,2,4-oxadiazolyl and 1,2,4-oxadiazolyl(46) HET-1 is
pyrazolyl(47) HET-1 is pyridyl or pyrazinyl(48) HET-1 is pyrazinyl(49)
HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and
pyrazinyl;(50) R.sup.6 is selected from (1-4C)alkyl, halo,
hydroxy(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl and HET-4(51) R.sup.6
is selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl,
methoxymethyl, aminomethyl, N-methylaminomethyl, dimethylaminomethyl(52)
R.sup.6 is selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl,
(1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,
(1-4C)alkylamino(1-4C)alkyl, and di(1-4C)alkylamino(1-4C)alkyl(53)
R.sup.6 is selected from methyl, ethyl, bromo, chloro, fluoro,
aminomethyl, N-methylaminomethyl, and dimethylaminomethyl(54) R.sup.6 is
selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl and
methoxymethyl(55) R.sup.6 is selected from methyl, ethyl, bromo, chloro
and fluoro(56) R.sup.6 is methyl(57) R.sup.6 is selected from methyl,
ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl,
dimethylaminomethyl, hydroxymethyl and methoxymethyl(58) R.sup.6 is
selected from methyl, ethyl, aminomethyl, N-methylaminomethyl,
dimethylaminomethyl, hydroxymethyl and methoxymethyl(59) R.sup.6 is
selected from (1-4C)alkyl and (1-4C)alkoxy(1-4C)alkyl(60) R.sup.6 is
selected from methyl, ethyl, isopropyl and methoxymethyl(61) when 2
substituents R.sup.6 are present, both are selected from methyl, ethyl,
bromo, chloro and fluoro; preferably both are methyl(62) R.sup.6 is
selected from (1-4C)alkylS(O)p(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl,
di(1-4C)alkylamino(1-4C)alkyl and HET-4

(63) 6 is HET-4

[0050](64) HET-4 is selected from furyl, pyrrolyl and thienyl(65) HET-4 is
furyl(66) R.sup.4 is hydrogen(67) R.sup.4 is (1-4C)alkyl [substituted by
1 or 2 substituents independently selected from HET-2, --OR.sup.5,
--SO.sub.2R.sup.5, (3-6C)cycloalkyl (optionally substituted with 1 group
selected from R.sup.7) and --C(O)NR.sup.5R.sup.5](68) R.sup.4 is
(1-4C)alkyl [substituted by 1 substituent selected from HET-2,
--OR.sup.5, --SO.sub.2R.sup.5, (3-6C)cycloalkyl and
--C(O)NR.sup.5R.sup.5],

(69) R.sup.4 is (1-4C)alkyl

[0051](70) R.sup.4 is (1-4C)alkyl substituted by --OR.sup.5 (71) R.sup.4
is (1-4C)alkyl substituted by HET-2(72) R.sup.4 is (3-6C)cycloalkyl,
particularly cyclopropyl or cyclobutyl(73) R.sup.4 is (3-6C)cycloalkyl
substituted by group selected from R.sup.7 (74) R.sup.4 is
(3-6C)cycloalkyl substituted by a group selected from --OR.sup.15 and
(1-4C)alkyl(75) R.sup.4 selected from (1-4C)alkyl and
(3-6C)cycloalkyl(76) R.sup.4 is selected from methyl, ethyl, cyclopropyl
and cyclobutyl

[0053]According to a further feature of the invention there is provided
the following preferred groups of compounds of the invention:

[0054]In a further aspect of the invention there is provided a compound of
Formula (I) as hereinbefore defined, wherein R.sup.4 is selected from
hydrogen, (1-4C)alkyl [optionally substituted by 1 or 2 substituents
independently selected from HET-2, --OR.sup.5, --SO.sub.2R.sup.5,
(3-6C)cycloalkyl (optionally substituted with 1 group selected from
R.sup.7) and --C(O)NR.sup.5R.sup.5] and HET-2.

[0055]In a further aspect of the invention there is provided a compound of
Formula (I) wherein:

R.sup.1 is hydroxymethyl;R.sup.2 is selected from --C(O)NR.sup.4R.sup.5,
--SO.sub.2NR.sup.4R.sup.5, --S(O).sub.pR.sup.4 and HET-2;HET-1 is a 5- or
6-membered, C-linked heteroaryl ring containing a nitrogen atom in the
2-position and optionally 1, 2 or 3 further ring heteroatoms
independently selected from O, N and S; which ring is optionally
substituted on an available carbon atom, or on a ring nitrogen atom
provided it is not thereby quaternised, with 1 or 2 substituents
independently selected from R.sup.6;HET-2 is a 5- or 6-membered, C- or
N-linked heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms
independently selected from O, N and S, wherein a --CH.sub.2-- group can
optionally be replaced by a --C(O)--, and wherein a sulphur atom in the
heterocyclic ring may optionally be oxidised to an S(O) or S(O).sub.2
group, which ring is optionally substituted on an available carbon or
nitrogen atom by 1 or 2 substituents independently selected from
R.sup.7;R.sup.3 is selected from halo, fluoromethyl, difluoromethyl,
trifluoromethyl, methyl, methoxy and cyano;R.sup.4 is selected from
hydrogen, (1-4C)alkyl, [optionally substituted by --OR.sup.5] and
HET-2;R.sup.5 is hydrogen or (1-4C)alkyl;or R.sup.4 and R.sup.5 together
with the nitrogen atom to which they are attached may form a 4-6 membered
heterocyclyl ring system as defined by HET-3;R.sup.6 is independently
selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl,
(1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,
(1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl and
HET-4;R.sup.7 is selected from 4-5 and (1-4C)alkyl;HET-3 is an N-linked,
4 to 6 membered, saturated or partially unsaturated heterocyclyl ring,
optionally containing 1 or 2 further heteroatoms (in addition to the
linking N atom) independently selected from O, N and S, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)-- and wherein a
sulphur atom in the ring may optionally be oxidised to an S(O) or
S(O).sub.2 group; which ring is optionally substituted on an available
carbon or nitrogen atom by 1 or 2 substituents independently selected
from R.sup.8;R.sup.8 is selected from --OR.sup.5 and (1-4C)alkyl; HET-4
is a 5- or 6-membered, C- or N-linked unsubstituted heteroaryl ring
containing 1, 2 or 3 ring heteroatoms independently selected from O, N
and S;p is (independently at each occurrence) 0, 1 or 2;m is 0 or 1;n is
0, 1 or 2;provided that when m is 0, then n is 1 or 2;or a salt, pro-drug
or solvate thereof.

[0056]In a further aspect of the invention there is provided a compound of
Formula (I) wherein:

R.sup.1 is hydroxymethyl;R.sup.2 is selected from C(O)NR.sup.4R.sup.5,
--SO.sub.2NR.sup.4R.sup.5, --S(O).sub.pR.sup.4 and HET-2;HET-1 is a 5- or
6-membered, C-linked heteroaryl ring containing a nitrogen atom in the
2-position and optionally 1, 2 or 3 further ring heteroatoms
independently selected from O, N and S; which ring is optionally
substituted on an available carbon atom, or on a ring nitrogen atom
provided it is not thereby quaternised, with 1 or 2 substituents
independently selected from R.sup.6;HET-2 is a 5- or 6-membered, C- or
N-linked heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms
independently selected from O, N and S, wherein a --CH.sub.2-- group can
optionally be replaced by a --C(O)--, and wherein a sulphur atom in the
heterocyclic ring may optionally be oxidised to an S(O) or S(O).sub.2
group, which ring is optionally substituted on an available carbon or
nitrogen atom by 1 or 2 substituents independently selected from
R.sup.7;R.sup.3 is selected from halo, fluoromethyl, difluoromethyl,
trifluoromethyl, methyl, methoxy and cyano;R.sup.4 is selected from
hydrogen, (1-4C)alkyl, [optionally substituted by --OR.sup.5] and
HET-2;R.sup.5 is hydrogen or (1-4C)alkyl;or R.sup.4 and R.sup.5 together
with the nitrogen atom to which they are attached may form a heterocyclyl
ring system as defined by HET-3;R.sup.6 is independently selected from
(1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl,
(1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,
(1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl and
HET-4;R.sup.7 is selected from --OR.sup.5 and (1-4C)alkyl;HET-3 is an
N-linked, 4 to 6 membered, saturated or partially unsaturated
heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in
addition to the linking N atom) independently selected from O, N and S,
wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)-- and
wherein a sulphur atom in the ring may optionally be oxidised to an S(O)
or S(O).sub.2 group; which ring is optionally substituted on an available
carbon or nitrogen atom by 1 or 2 substituents independently selected
from R.sup.8; orHET-3 is an N-linked, 7 membered, saturated or partially
unsaturated heterocyclyl ring, optionally containing 1 further heteroatom
(in addition to the linking N atom) independently selected from O, S and
N, wherein a --CH.sub.2-- group can optionally be replaced by a
--C(O)--group and wherein a sulphur atom in the ring may optionally be
oxidised to an S(O) or S(O).sub.2 group; which ring is optionally
substituted on an available carbon or nitrogen atom by 1 or 2
substituents independently selected from R.sup.8; orHET-3 is an 6-10
membered bicyclic saturated or partially unsaturated heterocyclyl ring,
optionally containing 1 further nitrogen atom (in addition to the linking
N atom), wherein a --CH.sub.2-- group can optionally be replaced by a
--C(O)--; which ring is optionally substituted on an available carbon or
nitrogen atom by 1 substituent selected from R.sup.3;R.sup.8 is selected
from --OR.sup.5 and (1-4C)alkyl;HET-4 is a 5- or 6-membered, C- or
N-linked unsubstituted heteroaryl ring containing 1, 2 or 3 ring
heteroatoms independently selected from O, N and S;p is (independently at
each occurrence) 0, 1 or 2;m is 0 or 1;n is 0, 1 or 2;provided that when
m is 0, then n is 1 or 2;or a salt, pro-drug or solvate thereof.

[0057]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein:

R.sup.1 is hydroxymethyl;R.sup.2 is selected from C(O)NR.sup.4R.sup.5,
--SO.sub.2NR.sup.4R.sup.5, --S(O).sub.pR.sup.4 and HET-2;HET-1 is a 5- or
6-membered, C-linked heteroaryl ring containing a nitrogen atom in the
2-position and optionally 1 or 2 further ring heteroatoms independently
selected from O, N and S; which ring is optionally substituted on an
available carbon atom, or on a ring nitrogen atom provided it is not
thereby quaternised, with 1 or 2 substituents independently selected from
R.sup.6;HET-2 is a 4-, 5- or 6-membered, C- or N-linked heterocyclyl ring
containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and
S, wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)--,
and wherein a sulphur atom in the heterocyclic ring may optionally be
oxidised to an S(O) or S(O).sub.2 group, which ring is optionally
substituted on an available carbon or nitrogen atom by 1 or 2
substituents independently selected from R.sup.7;R.sup.3 is selected from
halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and
cyano;R.sup.4 is selected from (1-4C)alkyl [substituted by 1 or 2
substituents independently selected from HET-2, --SO.sub.2R.sup.5,
(3-6C)cycloalkyl (optionally substituted with 1 group selected from
R.sup.7) and --C(O)NR.sup.5R.sup.5];R.sup.5 is hydrogen or (1-4C)alkyl;or
R.sup.4 and R.sup.5 together with the nitrogen atom to which they are
attached may form a 4-6 membered heterocyclyl ring system as defined by
HET-3;R.sup.6 is independently selected from (1-4C)alkyl, halo,
hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C alkyl,
amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl
di(1-4C)alkylamino(1-4C)alkyl and HET-4; it is selected from
--C(O)(1-4C)alkyl, --C(O)NR.sup.4R.sup.5, (1-4C)alkoxy(1-4C)alkyl,
hydroxy(1-4C)alkyl and --S(O)pR.sup.5;HET-3 is an N-linked, 4 to 6
membered, saturated or partially unsaturated heterocyclyl ring,
optionally containing 1 or 2 further heteroatoms (in addition to the
linking N atom) independently selected from O, N and S, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)-- and wherein a
sulphur atom in the ring may optionally be oxidised to an S(O)
orS(O).sub.2 group; which ring is optionally substituted on an available
carbon or nitrogen atom by 1 or 2 substituents independently selected
from R.sup.8;R.sup.8 is selected from --C(O)(1-4C)alkyl,
--C(O)NR.sup.4R.sup.5, (1-4C)alkylamino, di(1-4C)alkylamino, HET-3
(wherein said ring is unsubstituted), (1-4C)alkoxy(1-4C)alkyl,
hydroxyl(1-4C)alkyl and --S(O)pR.sup.5;HET-4 is a 5- or 6-membered C- or
N-linked unsubstituted heteroaryl ring containing 1, 2 or 3 ring
heteroatoms independently selected from O, N and S;p is (independently at
each occurrence) 0, 1 or 2;m is 0 or 1;n is 0, 1 or 2;provided that when
m is 0, then n is 1 or 2;or a salt, pro-drug or solvate thereof.

[0058]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein:

R.sup.1 is hydroxymethyl;R.sup.2 is selected from C(O)NR.sup.4R.sup.5,
--SO.sub.2NR.sup.4R.sup.5, --S(O).sub.pR.sup.4 and HET-2;HET-1 is a 5- or
6-membered, C-linked heteroaryl ring containing a nitrogen atom in the
2-position and optionally 1 or 2 further ring heteroatoms independently
selected from O, N and S; which ring is optionally substituted on an
available carbon atom, or on a ring nitrogen atom provided it is not
thereby quaternised, with 1 or 2 substituents independently selected from
R.sup.6;HET-2 is a 4-, 5- or 6-membered, C- or N-linked heterocyclyl ring
containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and
S, wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)--,
and wherein a sulphur atom in the heterocyclic ring may optionally be
oxidised to an S(O) or S(O).sub.2 group, which ring is optionally
substituted on an available carbon or nitrogen atom by 1 or 2
substituents independently selected from R.sup.7;R.sup.3 is selected from
halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and
cyano;R.sup.4 is selected from (1-4C)alkyl [substituted by 1 or 2
substituents independently selected from HET-2, --SO.sub.2R.sup.5,
(3-6C)cycloalkyl (optionally substituted with 1 group selected from
R.sup.7) and --C(O)NR.sup.5R.sup.5];R.sup.5 is hydrogen or (1-4C)alkyl,or
R.sup.4 and R.sup.5 together with the nitrogen atom to which they are
attached may form a heterocyclyl ring system as defined by HET-3;R.sup.6
is independently selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl,
(1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,
(1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl and
HET-4;R.sup.7 is selected from --C(O)(1-4C)alkyl --C(O)NR.sup.4R.sup.5,
(1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl and S(O)pR.sup.5;HET-3 is an
N-linked, 4 to 6 membered, saturated or partially unsaturated
heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in
addition to the linking N atom) independently selected from O, N and S,
wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)-- and
wherein a sulphur atom in the ring may optionally be oxidised to an S(O)
or S(O).sub.2 group; which ring is optionally substituted on an available
carbon or nitrogen atom by 1 or 2 substituents independently selected
from R.sup.8; orHET-3 is an N-linked, 7 membered, saturated or partially
unsaturated heterocyclyl ring, optionally containing 1 further heteroatom
(in addition to the linking N atom) independently selected from O, S and
N, wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)--
group and wherein a sulphur atom in the ring may optionally be oxidised
to an S(O) or S(O).sub.2 group; which ring is optionally substituted on
an available carbon or nitrogen atom by 1 or 2 substituents independently
selected from R.sup.8; orHET-3 is an 6-10 membered bicyclic saturated or
partially unsaturated heterocyclyl ring, optionally containing 1 further
nitrogen atom (in addition to the linking N atom), wherein a --CH.sub.2--
group can optionally be replaced by a --C(O)--; which ring is optionally
substituted on an available carbon or nitrogen atom by 1 substituent
selected from R.sup.3;R.sup.8 is selected from --C(O)(1-4C)alkyl,
--C(O)NR.sup.4R.sup.5, (1-4)alkylamino, di(1-4C)alkylamino, HET-3
(wherein said ring is unsubstituted), (1-4C)alkoxy(1-4C)alkyl,
hydroxy(1-4C)alkyl and S(O)pR.sup.5;HET-4 is a 5- or 6-membered, C- or
N-linked unsubstituted heteroaryl ring containing 1, 2 or 3 ring
heteroatoms independently selected from O, N and S;p is (independently at
each occurrence) 0, 1 or 2;m is 0 or 1;n is 0, 1 or 2;provided that when
m is 0, then n is 1 or 2;or a salt, pro-drug or solvate thereof.

[0059]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is a 5- or
6-membered heteroaryl ring, and is optionally substituted by 1 or 2
groups selected from R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5 or --SO.sub.2NR.sup.4R.sup.5;

[0060]R.sup.3 is halo or trifluoromethyl;R.sup.4 is (1-4C)alkyl
[optionally substituted by 1 or 2 substituents independently selected
from HET-2, --OR.sup.5, SO.sub.2R.sup.5, (3-6C)cycloalkyl (optionally
substituted with 1 group selected from R.sup.7) and
--C(O)NR.sup.5R.sup.5];R.sup.5 is hydrogen or methyl;R.sup.6 is selected
from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl,
(1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,
(1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl;HET-2 is a 5-
or 6-membered heterocyclyl ring as hereinbefore defined, containing 1 or
2 heteroatoms independently selected from O, N and S, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)--, and wherein
a sulphur atom in the heterocyclic ring may optionally be oxidised to an
S(O) or S(O).sub.2 group, which ring is optionally substituted on an
available carbon or nitrogen atom by 1 or 2 substituents independently
selected from R.sup.7; andR.sup.7; is selected from --OR.sup.5 and
(1-4C)alkyl;or a salt, pro-drug or solvate thereof.

[0061]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is a 5- or
6-membered heteroaryl ring, and is optionally substituted by 1 or 2
groups selected from R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5 or --SO.sub.2NR.sup.4R.sup.5:

[0062]R.sup.3 is halo or trifluoromethyl;R.sup.4 is (1-4C)alkyl
[optionally substituted by 1 or 2 substituents independently selected
from HET-2, --OR.sup.5, --SO.sub.2R.sup.5, (3-6C)cycloalkyl (optionally
substituted with 1 group selected from R.sup.7) and
--C(O)NR.sup.5R.sup.5];R.sup.5 is hydrogen or methyl;R.sup.6 is selected
from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl,
aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;HET-2 is a 5-
or 6-membered heterocyclyl ring as hereinbefore defined, containing 1 or
2 heteroatoms independently selected from O, N and S, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)--, and wherein
a sulphur atom in the heterocyclic ring may optionally be oxidised to an
S(O) or S(O).sub.2 group, which ring is optionally substituted on an
available carbon or nitrogen atom by 1 or 2 substituents independently
selected from R.sup.7; andR.sup.7 is selected from --OR.sup.5 and
(1-4C)alkyl;or a salt, pro-drug or solvate thereof.

[0063]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl and oxadiazolyl, and is optionally substituted by 1 or 2
groups selected from R.sup.6;

[0067]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl and oxadiazolyl, and is optionally substituted by a group
selected from R.sup.6;

[0069]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl, and is optionally
substituted by a group selected from R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5 or --SO.sub.2NR.sup.4R.sup.5;

[0070]R.sup.3 is halo or trifluoromethyl;R.sup.4 is (1-4C)alkyl
[optionally substituted by 1 or 2 substituents independently selected
from HET-2, --OR.sup.5, --SO.sub.2R.sup.5, (3-6C)cycloalkyl and
--C(O)NR.sup.5R.sup.5];R.sup.5 is hydrogen or methyl;R.sup.6 is selected
from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl,
aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;HET-2 is
selected from furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl,
pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl,
oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, 1,2,4-triazolyl and
1,2,3-triazolyl, and is optionally substituted by a group selected from
R.sup.7; andR.sup.7 is selected from --OR.sup.5 and (1-4C)alkyl;or a
salt, pro-drug or solvate thereof.

[0071]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl
and oxadiazolyl, and is optionally substituted by a group selected from
R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5 or --SO.sub.2NR.sup.4R.sup.5;

[0072]R.sup.3 is halo or trifluoromethyl;R.sup.4 is selected from
hydrogen, (1-4C)alkyl [optionally substituted by --OR.sup.5],
(3-6C)cycloalkyl (optionally substituted with 1 group selected from
R.sup.7) and HET-2;R.sup.5 is hydrogen or methyl;R.sup.6 is selected from
methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl,
aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;HET-2 is
selected from morpholino, furyl, imidazolyl, isoxazolyl, oxadiazolyl,
piperidinyl, piperazinyl, 3-oxopiperazinyl, pyrrolidinyl, 2-pyrrolidonyl,
tetrahydropyranyl, 1,1-dioxotetrahydrothienyl, and 2-oxoimidazolidinyl,
and is optionally substituted by a group selected from R.sup.7;
andR.sup.7 is selected from --OR.sup.5 and (1-4C)alkyl;or a salt,
pro-drug or solvate thereof.

[0073]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
pyridyl and pyridazinyl, and is optionally substituted by a group
selected from R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5 or --SO.sub.2NR.sup.4R.sup.5;

[0074]R.sup.3 is halo or trifluoromethyl;R.sup.4 is selected from
hydrogen, (1-4C)alkyl [optionally substituted by --OR.sup.5],
(3-6C)cycloalkyl (optionally substituted with 1 group selected from
R.sup.7) and HET-2;R.sup.5 is hydrogen or methyl;R.sup.6 is selected from
methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl,
aminomethyl, N-methylaminomethyl, and dimethylaminomethyl:HET-2 is
selected from morpholino, furyl, imidazolyl, isoxazolyl, oxadiazolyl,
piperidinyl, piperazinyl, 3-oxopiperazinyl, pyrrolidinyl, 2-pyrrolidonyl,
tetrahydropyranyl, 1,1-dioxotetrahydrothienyl, and 2-oxoimidazolidinyl,
and is optionally substituted by a group selected from R.sup.7;
andR.sup.7 is selected from --OR.sup.5 and (1-4C)alkyl;or a salt,
pro-drug or solvate thereof.

[0075]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl
and oxadiazolyl, and is optionally substituted by a group selected from
R.sup.6;

R.sup.2 is CONR.sup.4R.sup.5 or --SO.sub.2NR.sup.4R.sup.5;

[0076]R.sup.3 is halo or trifluoromethyl;R.sup.4 is selected from
(1-4C)alkyl [optionally substituted by --OR.sup.5], (3-6C)cycloalkyl
(optionally substituted with 1 group selected from R.sup.7) and
HET-2;R.sup.5 is hydrogen or methyl;R.sup.6 is selected from methyl,
ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl, aminomethyl,
N-methylaminomethyl, and dimethylaminomethyl;HET-2 is selected from
piperidinyl, piperazinyl, 3-oxopiperazinyl, 2-pyrrolidonyl,
2,5-dioxopyrrolidinyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl,
tetrahydropyranyl, 9-oxoimidazolidinyl, and 2,4-dioxoimidazolidinyl,
optionally substituted by R.sup.7; and

R.sup.7 is (1-4C)alkyl;

[0077]or a salt, pro-drug or solvate thereof.

[0078]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl
and oxadiazolyl, and is optionally substituted by a group selected from
R.sup.6;

R.sup.2 is <CONR.sup.4R.sup.5 or --SO.sub.2NR.sup.4R.sup.5,

[0079]R.sup.3 is halo or trifluoromethyl;R.sup.4 is selected from
(1-4C)alkyl [optionally substituted by --OR.sup.5], (3-6C)cycloalkyl
(optionally substituted with 1 group selected from R.sup.7) and
HET-2;R.sup.5 is hydrogen or methyl;R.sup.6 is selected from methyl,
ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl, aminomethyl,
N-methylaminomethyl, and dimethylaminomethyl;HET-2 is piperidinyl or
piperazinyl, and is optionally substituted by R.sup.7; and

R.sup.7 is (1-4C)alkyl;

[0080]or a salt pro-drug or solvate thereof.

[0081]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0;HET-1 is selected from
thiazolyl, thiadiazolyl and pyrazolyl, and is optionally substituted by a
group selected from R.sup.6;

R.sup.2 is CONR.sup.4R.sup.5;

[0082]R.sup.4 is piperidinyl, optionally substituted with methyl;R.sup.5
is hydrogen or methyl;R.sup.6 is methyl;or a salt, pro-drug or solvate
thereof.

[0083]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
pyridyl and pyridazinyl, and is optionally substituted by a group
selected from R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5 or --SO.sub.2NR.sup.4R.sup.5;

[0084]R.sup.3 is halo or trifluoromethyl;R.sup.4 is selected from
(1-4C)alkyl [optionally substituted by --OR.sup.5] and HET-2;R.sup.5 is
hydrogen or methyl;R.sup.6 is selected from methyl, ethyl, bromo, chloro,
fluoro, hydroxymethyl, methoxymethyl, aminomethyl, N-methylaminomethyl,
and dimethylaminomethyl;HET-2 is selected from piperidinyl, piperazinyl,
3-oxopiperazinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl,
2-oxazolidinonyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl,
tetrahydropyranyl, 2-oxoimidazolidinyl, and 2,4-dioxoimidazolidinyl, and
is optionally substituted by R.sup.7; and

R.sup.7 is (1-4C)alkyl;

[0085]or a salt, pro-drug or solvate thereof.

[0086]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
pyridyl and pyridazinyl, and is optionally substituted by a group
selected from R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5 or --SO.sub.2NR.sup.4R.sup.5;

[0087]R.sup.3 is halo or trifluoromethyl;R.sup.4 is selected from
(1-4C)alkyl [optionally substituted by --OR.sup.5] and HET-2;R.sup.5 is
hydrogen or methyl;R.sup.6 is selected from methyl, ethyl, bromo, chloro,
fluoro, hydroxymethyl, methoxymethyl, aminomethyl, N-methylaminomethyl,
and dimethylaminomethyl;HET-2 is piperidinyl or piperazinyl, optionally
substituted by R.sup.7; and

R.sup.7 is (1-4C)alkyl;

[0088]or a salt, pro-drug or solvate thereof.

[0089]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl
and oxadiazolyl, and is optionally substituted by a group selected from
R.sup.6;

R.sup.2 is CONR.sup.4R.sup.5 or --SO.sub.2NR.sup.4R.sup.5;

[0090]R.sup.3 is halo or trifluoromethyl;R.sup.4 and R.sup.5 together with
the nitrogen to which they are attached form a morpholino, piperidinyl,
piperazinyl, pyrrolidinyl or azetidinyl ring, which ring is optionally
substituted on a carbon or nitrogen atom by R.sup.8;R.sup.6 is selected
from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl,
aminomethyl, N-methylaminomethyl, and dimethylaminomethyl,R.sup.8 is
selected from hydroxy, (1-4C)alkoxy and (1-4C)alkyl;or a salt, pro-drug
or solvate thereof.

[0091]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl
and oxadiazolyl, and is optionally substituted by a group selected from
R.sup.6;

R.sup.2 is CONR.sup.4R.sup.5 or --SO.sub.2NR.sup.4R.sup.5;

[0092]R.sup.3 is halo or trifluoromethyl;R.sup.4 and R.sup.5 together with
the nitrogen to which they are attached form a morpholino, piperidinyl,
piperazinyl, pyrrolidinyl or azetidinyl ring, which ring is optionally
substituted on a carbon or nitrogen atom by R.sup.8;R.sup.6 is selected
from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl,
aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;R.sup.5 is
pyrrolidine or piperidine;or a salt, pro-drug or solvate thereof.

[0093]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl
and oxadiazolyl, and is optionally substituted by a group selected from
R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5 or --SO.sub.2CNR.sup.4R.sup.5:

[0094]R.sup.3 is halo or trifluoromethyl;R.sup.4 and R.sup.5 together with
the nitrogen to which they are attached form a morpholino, piperidinyl,
piperazinyl, pyrrolidinyl or azetidinyl ring, which ring is optionally
substituted on a carbon or nitrogen atom by (1-4C)alkyl;R.sup.6 is
selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl,
methoxymethyl, aminomethyl, N-methylaminomethyl, and
dimethylaminomethyl;or a salt, pro-drug or solvate thereof.

[0095]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
pyridyl and pyridazinyl, optionally substituted by a group selected from
R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5 or --SO.sub.2NR.sup.4R.sup.5;

[0096]R.sup.3 is halo or trifluoromethyl;R.sup.4 and R.sup.5 together with
the nitrogen to which they are attached form a morpholino, piperidinyl,
piperazinyl, pyrrolidinyl or azetidinyl ring, which ring is optionally
substituted on a carbon or nitrogen atom by (1-4C)alkyl;R.sup.6 is
selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl,
methoxymethyl, aminomethyl, N-methylaminomethyl, and
dimethylaminomethyl;or a salt, pro-drug or solvate thereof.

[0097]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0;HET-1 is selected from
thiazolyl, thiadiazolyl and pyrazolyl, and is optionally substituted by a
group selected from R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5;

[0098]R.sup.4 and R.sup.5 together with the nitrogen to which they are
attached form a piperidinyl, or piperazinyl ring, which ring is
optionally substituted on a carbon or nitrogen atom by (1-4C)alkyl or by
a pyrrolidinyl ring;R.sup.6 is selected from methyl, ethyl, bromo,
chloro, fluoro, hydroxymethyl, methoxymethyl, aminomethyl,
N-methylaminomethyl, and dimethylaminomethyl;or a salt, pro-drug or
solvate thereof.

[0099]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0;HET-1 is selected from
thiazolyl, thiadiazolyl and pyrazolyl, and is optionally substituted by a
group selected from R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5;

[0100]R.sup.4 and R.sup.5 together with the nitrogen to which they are
attached form an azetidinyl ring which ring is optionally substituted on
a carbon atom by hydroxy;R.sup.6 is selected from methyl, ethyl, bromo,
chloro, fluoro, hydroxymethyl, methoxymethyl, aminomethyl,
N-methylaminomethyl, and dimethylaminomethyl;or a salt, pro-drug or
solvate thereof.

[0101]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0;HET-1 is selected from
thiazolyl, thiadiazolyl, pyrazolyl and pyrazinyl, and is optionally
substituted by a group selected from R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5;

[0102]R.sup.4 and R.sup.5 together with the nitrogen to which they are
attached form an azetidinyl ring which ring is optionally substituted on
a carbon atom by methyl, methoxy or isopropoxy;R.sup.6 is selected from
methyl, ethyl, isopropyl and methoxymethyl;or a salt, pro-drug or solvate
thereof.

[0103]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 1;HET-1 is selected from
thiazolyl, thiadiazolyl and pyrazolyl, and is optionally substituted by a
group selected from R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5;

[0104]R.sup.3 is chloro or fluoro;R.sup.4 and R.sup.5 together with the
nitrogen to which they are attached form an azetidinyl ring which ring is
optionally substituted on a carbon atom by hydroxy;R.sup.6 is selected
from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl,
aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;or a salt,
pro-drug or solvate thereof.

[0105]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0;HET-1 is selected from
thiazolyl, thiadiazolyl and pyrazolyl, and is optionally substituted by a
group selected from R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5;

[0106]R.sup.4 and R.sup.5 together with the nitrogen to which they are
attached form a 7-membered ring HET-3 which ring is optionally
substituted on a carbon or nitrogen atom by methyl;R.sup.6 is selected
from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl,
aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;or a salt,
pro-drug or solvate thereof.

[0107]In a further aspect of the invention is provided a compound of the
formula (J) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0;HET-1 is selected from
thiazolyl, thiadiazolyl and pyrazolyl, and is optionally substituted by a
group selected from R.sup.6;

R.sup.2 is --CONR.sup.4R.sup.5;

[0108]R.sup.4 and R.sup.5 together with the nitrogen to which they are
attached form a 6-10 membered bicyclic heterocyclic ring HET-3 as
hereinbefore defined, which ring is optionally substituted by hydroxy or
methyl;R.sup.6 is selected from methyl, ethyl, bromo, chloro, fluoro,
hydroxymethyl, methoxymethyl, aminomethyl, N-methylaminomethyl, and
dimethylaminomethyl;or a salt, pro-drug or solvate thereof.

[0109]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is a 5- or
6-membered heteroaryl ring, optionally substituted by 1 or 2 groups
independently selected from R.sup.6;

R.sup.2 is --S(O)pR.sup.4;

[0110]p is 1 or 2;R.sup.3 is halo or trifluoromethyl;R.sup.4 is
(1-4C)alkyl [optionally substituted by 1 or 2 substituents independently
selected from HET-2, --OR.sup.5, --SO.sub.2R.sup.5, (3-6C)cycloalkyl
(optionally substituted with 1 group selected from R.sup.7) and
--C(O)NR.sup.5R.sup.5];R.sup.5 is hydrogen or methyl;R.sup.6 is selected
from (1-4C)alkyl, halo, hydroxy(T-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl,
(1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,
(1-4C)alkylamino(1-4C)alkyl and di(1-4C)alkylamino(1-4C)alkyl;HET-2 is a
5- or 6-membered heterocyclyl ring, containing 1 or 2 heteroatoms
independently selected from O, N and S, wherein a --CH.sub.2-- group can
optionally be replaced by a --C(O)--, and wherein a sulphur atom in the
heterocyclic ring may optionally be oxidised to an S(O) or S(O).sub.2
group, which ring is optionally substituted on an available carbon or
nitrogen atom by 1 or 2 substituents independently selected from R.sup.7;
andR.sup.7 is selected from --OR.sup.5 and (1-4C)alkyl;or a salt,
pro-drug or solvate thereof.

[0111]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is a 5- or
6-membered heteroaryl ring, optionally substituted by 1 or 2 groups
independently selected from R.sup.6;

R.sup.2 is --S(O)pR.sup.4;

[0112]p is 1 or 2;R.sup.3 is halo or trifluoromethyl;R.sup.4 is
(1-4C)alkyl [optionally substituted by 1 or 2 substituents independently
selected from HET-2, --OR.sup.5, --SO.sub.2R.sup.5, (3-6C)cycloalkyl
(optionally substituted with 1 group selected from R.sup.7) and
--C(O)NR.sup.5R.sup.5];R.sup.5 is hydrogen or methyl;R.sup.6 is selected
from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl,
aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;HET-2 is a 5-
or 6-membered heterocyclyl ring, containing 1 or 2 heteroatoms
independently selected from O, N and 8, wherein a --CH.sub.2-- group can
optionally be replaced by a --C(O)-- and wherein a sulphur atom in the
heterocyclic ring may optionally be oxidised to an S(O) or S(O).sub.2
group, which ring is optionally substituted on an available carbon or
nitrogen atom by 1 or 2 substituents independently selected from R.sup.7;
andR.sup.7 is selected from --OR.sup.5 and (1-4C)alkyl;or a salt,
pro-drug or solvate thereof.

[0113]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl and oxadiazolyl, and is optionally substituted by a group
selected from R.sup.6;

R.sup.2 is --S(O)pR.sup.4;

[0114]p is 1 or 2;R.sup.3 is halo or trifluoromethyl;R.sup.4 is
(1-4C)alkyl [optionally substituted by 1 or 2 substituents independently
selected from HET-2, --OR.sup.5, --SO.sub.2R.sup.5, (3-6C)cycloalkyl and
--C(O)NR.sup.5R.sup.5];R.sup.5 is hydrogen or methyl;R.sup.6 is selected
from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl,
aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;HET-2 is
selected from azetidinyl, morpholino, morpholinyl, piperidinyl,
piperazinyl, 3-oxopiperazinyl, thiomorpholinyl, pyrrolidinyl,
pyrrolidonyl, 2,5-dioxopyrrolidinyl, 1,1-dioxotetrahydrothienyl,
2-oxazolidinonyl, 2-oxotetrahydrofuranyl, tetrahydrofranyl,
tetrahydropyranyl, 1,1-dioxothiomorpholino, 1,3-dioxolanyl,
2-oxoimidazolidinyl, 2,4-dioxoimidazolidinyl, pyranyl and 4-pyridonyl,
and is optionally substituted by a group selected from R.sup.7;
andR.sup.7 is selected from --OR.sup.5 and (1-4C)alkyl;or a salt,
pro-drug or solvate thereof.

[0115]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl and oxadiazolyl, and is optionally substituted by a group
selected from R.sup.6;

R.sup.2 is --S(O)pR.sup.4;

[0116]p is 1 or 2;R.sup.3 is halo or trifluoromethyl;R.sup.4 is selected
from hydrogen, (1-4C)alkyl [optionally substituted by --OR.sup.5],
(3-6C)cycloalkyl (optionally substituted with 1 group selected from
R.sup.7) and HET-2;R.sup.5 is hydrogen or methyl;R.sup.6 is selected from
methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl,
aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;HET-2 is
selected from furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl,
pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl,
oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, 1,2,4-triazolyl and
1,2,3-triazolyl, and is optionally substituted by a group selected from
R.sup.7; andR.sup.7 is selected from --OR.sup.5 and (1-4C)alkyl;or a
salt, pro-drug or solvate thereof.

[0117]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl, and is optionally
substituted by a group selected from R.sup.6;

R.sup.2 is --S(O)pR.sup.4;

[0118]p is 1 or 2;R.sup.3 is halo or trifluoromethyl;R.sup.4 is
(1-4C)alkyl [optionally substituted by 1 or 2 substituents independently
selected from HET-2, --OR.sup.5, --SO.sub.2R.sup.5, (3-6C)cycloalkyl and
--C(O)NR.sup.5R.sup.5];R.sup.5 is hydrogen or methyl;R.sup.6 is selected
from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl,
aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;HET-2 is
selected from azetidinyl, morpholino, morpholinyl, piperidinyl,
piperazinyl, 3-oxopiperazinyl, thiomorpholinyl, pyrrolidinyl,
pyrrolidonyl, 2,5-dioxopyrrolidinyl, 1,1-dioxotetrahydrothienyl,
2-oxazolidinonyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl,
tetrahydropranyl, 1,1-dioxothiomorpholino, 1,3-dioxolanyl,
2-oxoimidazolidinyl, 2,4-dioxoimidazolidinyl, pyranyl and 4-pyridonyl,
and is optionally substituted by a group selected from R.sup.7;
andR.sup.7 is selected from --OR.sup.5 and (1-4C)alkyl;or a salt,
pro-drug or solvate thereof.

[0119]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl, and is optionally
substituted by a group selected from R.sup.6;

R.sup.2 is S(O)pR.sup.4;

[0120]p is 1 or 2;R.sup.3 is halo or trifluoromethyl;R.sup.4 is selected
from hydrogen, (1-4C)alkyl [optionally substituted by --OR.sup.5],
(3-6C)cycloalkyl (optionally substituted with 1 group selected from
R.sup.7) and HET-2;R.sup.5 is hydrogen or methyl;R.sup.6 is selected from
methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N-methylaminomethyl,
and dimethylaminomethyl;HET-2 is selected from furyl, thienyl, thiazolyl,
isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl,
imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl,
1,2,4-triazolyl and 1,2,3-triazolyl, and is optionally substituted by a
group selected from R.sup.7; andR.sup.7 is selected from --OR.sup.5 and
(1-4C)alkyl;or a salt, pro-drug or solvate thereof.

[0121]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl and oxadiazolyl, and is optionally substituted by a group
selected from R.sup.6;

[0133]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is for 1;HET-1 is a 5- or 6-membered
heteroaryl ring, and is optionally substituted by a group selected from
6;

R.sup.2 is HET-2;

[0134]R.sup.3 is halo or trifluoromethyl;R.sup.5 is hydrogen or
(1-4C)alkyl;R.sup.6 is methyl;HET-2 is a 5- or 6-membered heterocyclyl
ring, containing 1 or 2 heteroatoms independently selected from O, N and
S, wherein a --CH.sub.2-- group can optionally be replaced by a --C(O)--
and wherein a sulphur atom in the heterocyclic ring may optionally be
oxidised to an S(O) or S(O).sub.2 group, which ring is optionally
substituted on an available carbon or nitrogen atom by 1 or 2
substituents independently selected from R.sup.7; andR.sup.7 is selected
from --OR.sup.5 and (1-4C)alkyl;or a salt, pro-drug or solvate thereof.

[0135]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl and oxadiazolyl, and is optionally substituted by a group
R.sup.6;

R.sup.2 is HET-2;

[0136]R.sup.3 is halo or trifluoromethyl;R.sup.5 is hydrogen or
methyl;R.sup.6 is methyl;HET-2 is selected from azetidinyl, morpholino,
morpholinyl, piperidinyl, piperazinyl, 3-oxopiperazinyl, thiomorpholinyl,
pyrrolidinyl, pyrrolidonyl, 2,5-dioxopyrrolidinyl,
1,1-dioxotetrahydrothienyl, 2-oxazolidinonyl, 2-oxotetrahydrofuranyl,
tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxothiomorpholino,
1,3-dioxolanyl, 2-oxoimidazolidinyl, 2,4-dioxoimidazolidinyl, pyranyl and
4-pyridonyl, and is optionally substituted by a group selected from
R.sup.7; andR.sup.7 is selected from --OR.sup.5 and (1-4C)alkyl;or a
salt, pro-drug or solvate thereof.

[0137]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl and oxadiazolyl, and is optionally substituted by a group
R.sup.6;

R.sup.2 is HET-2;

[0138]R.sup.3 is halo or trifluoromethyl;R.sup.5 is hydrogen or
methyl;R.sup.6 is methyl;HET-2 is selected from furyl, thienyl,
thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl,
pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl,
pyrrolyl, 1,2,4-triazolyl and 1,2,3-triazolyl, and is optionally
substituted by a group selected from R.sup.7; andR.sup.7 is selected from
--OR.sup.5 and (1-4C)alkyl;or a salt, pro-drug or solvate thereof.

[0139]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl, and is optionally
substituted by a group R.sup.6;

R.sup.2 is HET-2;

[0140]R.sup.3 is halo or trifluoromethyl;R.sup.5 is hydrogen or
methyl;R.sup.6 is methyl;HET-2 is selected from azetidinyl, morpholino,
morpholinyl, piperidinyl, piperazinyl, 3-oxopiperazinyl, thiomorpholinyl,
pyrrolidinyl, pyrrolidonyl, 2,5-dioxopyrrolidinyl,
1,1-dioxotetrahydrothienyl, 2-oxazolidinonyl, 2-oxotetrahydrofranyl,
tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxothiomorpholino,
1,3-dioxolanyl, 2-oxoimidazolidinyl, 2,4-dioxoimidazolidinyl, pyranyl and
4-pyridonyl, and is optionally substituted by a group selected from
R.sup.7; andR.sup.7 is selected from --OR.sup.5 and (1-4C)alkyl;or a
salt, pro-drug or solvate thereof.

[0141]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl, and is optionally
substituted by a group R.sup.6;

R.sup.2 is HET-2;

[0142]R.sup.3 is halo or trifluoromethyl;R.sup.5 is hydrogen or
methyl;R.sup.6 is methyl;HET-2 is selected from furyl, thienyl,
thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl,
pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl,
pyrrolyl, 1,2,4-triazolyl and 1,2,3-triazolyl, and is optionally
substituted by a group selected from R.sup.7; andR.sup.7 is selected from
--OR.sup.5 and (1-4C)alkyl;or a salt, pro-drug or solvate thereof.

[0143]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl and oxadiazolyl, and is optionally substituted by a group
selected from R.sup.6;

[0146]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl and oxadiazolyl, and is optionally substituted by a group
selected from R.sup.6;

[0155]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0 or 1;HET-1 is selected from
thienyl, pyrazolyl, thiadiazolyl and pyrazinyl, and is optionally
substituted by a group selected from R.sup.6;R.sup.6 is selected from
methyl, ethyl, isopropyl and methoxymethyl;R.sup.2 is selected from
methylsulfonyl, azetidinylcarbonyl, dimethylaminocarbonyl, ethylsulfonyl,
dimethylaminosulfonyl and pyrrolidinylcarbonyl;R.sup.3 is selected from
fluoro, chloro and methoxy;or a salt, pro-drug or solvate thereof.

[0156]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0, 1 or 2;HET-1 is selected from
thienyl, pyrazolyl, thiadiazolyl and pyrazinyl, and is optionally
substituted by a group selected from R.sup.6;R.sup.6 is selected from
methyl, ethyl, isopropyl and methoxymethyl;R.sup.2 is selected from
methylsulfonyl, azetidinylcarbonyl, dimethylaminocarbonyl, ethylsulfonyl,
dimethylaminosulfonyl, methylazetidinylcarbonyl,
methoxyazetidinylcarbonyl, isopropoxyazetidinylcarbonyl,
azetidinylsulfonyl, cyclobutylsulfonyl, cyclopropylsulfonyl,
7-azabicyclo[2.2.1]hept-7-ylcarbonyl, 2-azabicyclo[2.1.1]hex-2-ylcarbonyl
and pyrrolidinylcarbonyl;R.sup.3 is selected from fluoro, chloro and
methoxy;or a salt, pro-drug or solvate thereof.

[0157]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 1 and n is 0, 1 or 2;HET-1 is selected from
thienyl, pyrazolyl, thiadiazolyl and pyrazinyl, and is optionally
substituted by a group selected from R.sup.6;R.sup.6 is selected from
methyl, ethyl, isopropyl and methoxymethyl;R.sup.2 is selected from
methylsulfonyl, azetidinylcarbonyl, dimethylaminocarbonyl, ethylsulfonyl,
dimethylaminosulfonyl, methylazetidinylcarbonyl,
methoxyazetidinylcarbonyl, isopropoxyazetidinylcarbonyl,
azetidinylsulfonyl, cyclobutylsulfonyl, cyclopropylsulfonyl and
pyrrolidinylcarbonyl;R.sup.3 is selected from fluoro, chloro and
methoxy;or a salt, pro-drug or solvate thereof.

[0158]In a further aspect of the invention is provided a compound of the
formula (I) as hereinbefore defined wherein

R.sup.1 is hydroxymethyl;m is 0 and n is 1 or 2;HET-1 is selected from
thienyl, pyrazolyl, thiadiazolyl and pyrazinyl, and is optionally
substituted by a group selected from R.sup.6;R.sup.6 is selected from
methyl, ethyl, isopropyl and methoxymethyl;R.sup.3 is selected from
fluoro, chloro and methoxy;or a salt, pro-drug or solvate thereof.

[0159]Further preferred compounds of the invention are each of the
Examples and/or Reference Examples, each of which provides a further
independent aspect of the invention. In further aspects, the present
invention also comprises any two or more compounds of the Examples and/or
Reference Examples.

[0447]In another aspect, particular compounds of the invention comprise
any one or more of:
[0448]3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-m-
ethylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
[0449]3-{[4-(azetidin-1-ylcarbonyl)-2-chlorophenyl]oxy}-5-{[(1S)-2-hydrox-
y-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
[0450]3-{[4-(azetidin-1-ylcarbonyl)phenyl]oxy}-5-{[(1S)-2-hydroxy-1-methy-
lethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;or a salt, pro-drug or
solvate thereof.

[0464]In a further aspect of the invention there is provided
[0465]3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-
-(1,2,4-oxadiazol-3-yl)phenoxy]benzamide.a salt, pro-drug or solvate
thereof.

[0466]The compounds of the invention may be administered in the form of a
pro-drug. A pro-drug is a bioprecursor or pharmaceutically acceptable
compound being degradable in the body to produce a compound of the
invention (such as an ester or amide of a compound of the invention,
particularly an in-vivo hydrolysable ester). Various forms of prodrugs
are known in the art. For examples of such prodrug derivatives, see:
[0467]a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and
Methods in Enzymology, Vol. 4, p. 309-396, edited by K. Widder, et au,
(Academic Press, 1985); [0468]b) A Textbook of Drug Design and
Development, edited by Krogsgaard-Larsen; [0469]c) H. Bundgaard, Chapter
5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191
(1991); [0470]d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38
(1992); [0471]e) H. Bundgaard, et al., Journal of Pharmaceutical
Sciences, 77, 285 (1988); and [0472]f) N. Kakeya, et al., Chem Pharm Bull
32, 692 (1984).

[0473]The contents of the above cited documents are incorporated herein by
reference.

[0474]Examples of pro-drugs are as follows. An in-vivo hydrolysable ester
of a compound of the invention containing a carboxy or a hydroxy group
is, for example, a pharmaceutically-acceptable ester which is hydrolysed
in the human or animal body to produce the parent acid or alcohol.
Suitable pharmaceutically-acceptable esters for carboxy include

[0475]An in-vivo hydrolysable ester of a compound of the invention
containing a hydroxy group includes inorganic esters such as phosphate
esters (including phosphoramidic cyclic esters) and .alpha.-acyloxyalkyl
ethers and related compounds which as a result of the in-vivo hydrolysis
of the ester breakdown to give the parent hydroxy group/s. Examples of
.alpha.-acyloxyalkyl ethers include acetoxymethoxy and
2,2-dimethylpropionyloxy-methoxy. A selection of in-vivo hydrolysable
ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl
and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl
carbonate esters), dialkylcarbamoyl and
N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),
dialkylaminoacetyl and carboxyacetyl.

[0476]A suitable pharmaceutically-acceptable salt of a compound of the
invention is, for example, an acid-addition salt of a compound of the
invention which is sufficiently basic, for example, an acid-addition salt
with, for example, an inorganic or organic acid, for example
hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric
or maleic acid. It will be understood that an acid addition salt may be
formed with any sufficiently basic group which may for example be in
HET-1 or may for example be a substituent R.sup.2. In addition a suitable
pharmaceutically-acceptable salt of a benzoxazinone derivative of the
invention which is sufficiently acidic is an alkali metal salt, for
example a sodium or potassium salt, an alkaline earth metal salt, for
example a calcium or magnesium salt, an ammonium salt or a salt with an
organic base which affords a physiologically-acceptable cation, for
example a salt with methylamine, dimethylamine, trimethylamine,
piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0477]A further feature of the invention is a pharmaceutical composition
comprising a compound of Formula (I) as defined above, or a salt, solvate
or prodrug thereof, together with a pharmaceutically-acceptable diluent
or carrier.

[0478]According to another aspect of the invention there is provided a
compound of Formula (I) as defined above for use as a medicament.

[0479]Further according to the invention there is provided a compound of
Formula (I) for use in the preparation of a medicament for treatment of a
disease mediated through GLK, in particular type 2 diabetes.

[0480]The compound is suitably formulated as a pharmaceutical composition
for use in this way.

[0481]According to another aspect of the present invention there is
provided a method of treating GLK mediated diseases, especially diabetes,
by administering an effective amount of a compound of Formula (I) or
salt, solvate or pro-drug thereof, to a mammal in need of such treatment.

[0483]As discussed above, thus the GLK/GLKRP system can be described as a
potential "Diabesity" target (of benefit in both Diabetes and Obesity).
Thus, according to another aspect of the invention there if provided the
use of a compound of Formula (I) or salt, solvate or pro-drug thereof in
the preparation of a medicament for use in the combined treatment or
prevention of diabetes and obesity.

[0484]According to another aspect of the invention there is provided the
use of a compound of Formula (I) or salt, solvate or pro-drug thereof, in
the preparation of a medicament for use in the treatment or prevention of
obesity.

[0485]According to a further aspect of the invention there is provided a
method for the combined treatment of obesity and diabetes by
administering an effective amount of a compound of Formula (I) or salt,
solvate or pro-drug thereof, to a mammal in need of such treatment.

[0486]According to a further aspect of the invention there is provided a
method for the treatment of obesity by administering an effective amount
of a compound of Formula (I) or salt, solvate or pro-drug thereof to a
mammal in need of such treatment.

[0487]Compounds of the invention may be particularly suitable for use as
pharmaceuticals, for example because of favourable physical and/or
pharmacokinetic properties and/or toxicity profile.

[0488]The compositions of the invention may be in a form suitable for oral
use (for example as tablets, lozenges, hard or soft capsules, aqueous or
oily suspensions, emulsions, dispersible powders or granules, syrups or
elixirs), for topical use (for example as creams, ointments, gels, or
aqueous or oily solutions or suspensions), for administration by
inhalation (for example as a finely divided powder or a liquid aerosol),
for administration by insufflation (for example as a finely divided
powder) or for parenteral administration (for example as a sterile
aqueous or oily solution for intravenous, subcutaneous, intramuscular or
intramuscular dosing or as a suppository for rectal dosing). Dosage forms
suitable for oral use are preferred.

[0489]The compositions of the invention may be obtained by conventional
procedures using conventional pharmaceutical excipients, well known in
the art. Thus, compositions intended for oral use may contain, for
example, one or more colouring, sweetening, flavouring anchor
preservative agents.

[0490]Suitable pharmaceutically acceptable excipients for a tablet
formulation include, for example inert diluents such as lactose, sodium
carbonate calcium phosphate or calcium carbonate, granulating and
disintegrating agents such as corn starch or algenic acid; binding agents
such as starch; lubricating agents such as magnesium stearate, stearic
acid or talc; preservative agents such as ethyl or propyl
p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet
formulations may be uncoated or coated either to modify their
disintegration and the subsequent absorption of the active ingredient
within the gastrointestinal tract, or to improve their stability and/or
appearance, in either case, using conventional coating agents and
procedures well known in the art.

[0491]Compositions for oral use may be in the form of hard gelatin
capsules in which the active ingredient is mixed with an inert solid
diluent, for example, calcium carbonate, calcium phosphate or kaolin, or
as soft gelatin capsules in which the active ingredient is mixed with
water or an oil such as peanut oil, liquid paraffin, or olive oil.

[0492]Aqueous suspensions generally contain the active ingredient in
finely powdered form together with one or more suspending agents, such as
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum
tragacanth and gum acacia; dispersing or wetting agents such as lecithin
or condensation products of an alkylene oxide with fatty acids (for
example polyoxethylene stearate), or condensation products of ethylene
oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide
with partial esters derived from fatty acids and a hexitol such as
polyoxyethylene sorbitol monooleate, or condensation products of ethylene
oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide
with partial esters derived from fatty acids and a hexitol such as
polyoxyethylene sorbitol monooleate, or condensation products of ethylene
oxide with partial esters derived from fatty acids and hexitol
anhydrides, for example polyethylene sorbitan monooleate. The aqueous
suspensions may also contain one or more preservatives (such as ethyl or
propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),
colouring agents, flavouring agents, and/or sweetening agents (such as
sucrose, saccharine or aspartame).

[0493]Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil
or coconut oil) or in a mineral oil (such as liquid paraffin). The oily
suspensions may also contain a thickening agent such as beeswax, hard
paraffin or cetyl alcohol. Sweetening agents such as those set out above,
and flavouring agents may be added to provide a palatable oral
preparation. These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.

[0494]Dispersible powders and granules suitable for preparation of an
aqueous suspension by the addition of water generally contain the active
ingredient together with a dispersing or wetting agent, suspending agent
and one or more preservatives. Suitable dispersing or wetting agents and
suspending agents are exemplified by those already mentioned above.
Additional excipients such as sweetening, flavouring and colouring
agents, may also be present.

[0495]The pharmaceutical compositions of the invention may also be in the
form of oil-in-water emulsions. The oily phase may be a vegetable oil,
such as olive oil or arachis oil, or a mineral oil, such as for example
liquid paraffin or a mixture of any of these. Suitable emulsifing agents
may be, for example, naturally-occurring gums such as gum acacia or gum
tragacanth, naturally-occurring phosphatides such as soya bean, lecithin,
an esters or partial esters derived from fatty acids and hexitol
anhydrides (for example sorbitan monooleate) and condensation products of
the said partial esters with ethylene oxide such as polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening,
flavouring and preservative agents.

[0496]Syrups and elixirs may be formulated with sweetening agents such as
glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also
contain a demulcent, preservative, flavouring and/or colouring agent.

[0497]The pharmaceutical compositions may also be in the form of a sterile
injectable aqueous or oily suspension, which may be formulated according
to known procedures using one or more of the appropriate dispersing or
wetting agents and suspending agents, which have been mentioned above. A
sterile injectable preparation may also be a sterile injectable solution
or suspension in a non-toxic parenterally-acceptable diluent or solvent,
for example a solution in 1,3-butanediol.

[0498]Compositions for administration by inhalation may be in the form of
a conventional pressurised aerosol arranged to dispense the active
ingredient either as an aerosol containing finely divided solid or liquid
droplets. Conventional aerosol propellants such as volatile fluorinated
hydrocarbons or hydrocarbons may be used and the aerosol device is
conveniently arranged to dispense a metered quantity of active
ingredient.

[0500]The amount of active ingredient that is combined with one or more
excipients to produce a single dosage form will necessarily vary
depending upon the host treated and the particular route of
administration. For example, a formulation intended for oral
administration to humans will generally contain, for example, from 0.5 mg
to 2 g of active agent compounded with an appropriate and convenient
amount of excipients which may vary from about 5 to about 98 percent by
weight of the total composition. Dosage unit forms will generally contain
about 1 mg to about 500 mg of an active ingredient. For further
information on Routes of Administration and Dosage Regimes the reader is
referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry
(Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

[0501]The size of the dose for therapeutic or prophylactic purposes of a
compound of the Formula (I) will naturally vary according to the nature
and severity of the conditions, the age and sex of the animal or patient
and the route of administration, according to well known principles of
medicine.

[0502]In using a compound of the Formula (I) for therapeutic or
prophylactic purposes it will generally be administered so that a daily
dose in the range, for example, 0.5 mg to 75 mg per kg body weight is
received, given if required in divided doses. In general lower doses will
be administered when a parenteral route is employed. Thus, for example,
for intravenous administration, a dose in the range, for example, 0.5 mg
to 30 mg per kg body weight will generally be used. Similarly, for
administration by inhalation, a dose in the range, for example, 0.5 mg to
25 mg per kg body weight will be used. Oral administration is however
preferred.

[0503]The elevation of GLK activity described herein may be applied as a
sole therapy or in combination with one or more other substances and/or
treatments for the indication being treated. Such conjoint treatment may
be achieved by way of the simultaneous, sequential or separate
administration of the individual components of the treatment.
Simultaneous treatment may be in a single tablet or in separate tablets.
For example in the treatment of diabetes mellitus, chemotherapy may
include the following main categories of treatment:

[0504]According to another aspect of the present invention there is
provided individual compounds produced as end products in the Examples
set out below and salts, solvates and pro-drugs thereof.

[0505]A compound of the invention, or a salt thereof, may be prepared by
any process known to be applicable to the preparation of such compounds
or structurally related compounds. Functional groups may be protected and
deprotected using conventional methods. For examples of protecting groups
such as amino and carboxylic acid protecting groups (as well as means of
formation and eventual deprotection). see T. W. Greene and P. G. M. Wuts,
"Protective Groups in Organic Synthesis", Second Edition, John Wiley &
Sons, New York, 1991.

[0506]Processes for the synthesis of compounds of Formula (I) are provided
as a further feature of the invention. Thus, according to a further
aspect of the invention there is provided a process for the preparation
of a compound of Formula (I), which comprises a process a) to d) (wherein
the variables are as defined hereinbefore for compounds of Formula (I)
unless otherwise defined): [0507](a) reaction of an acid of Formula (III)
or activated derivative thereof with a compound of Formula (IV), wherein
R.sup.1 is hydroxymethyl or a protected version thereof;

##STR00010##

[0508]or [0509](b) reaction of a compound of Formula (V) with a compound
of Formula (VI),

##STR00011##

[0509]wherein X.sup.1 is a leaving group and X.sup.2 is a hydroxyl group
or X.sup.1 is a hydroxyl group and X.sup.2 is a leaving group, and
wherein R.sup.1 is hydroxymethyl or a protected version thereof; process
(b) could also be accomplished using the intermediate ester Formula
(VII), wherein P.sup.1 is a protecting group as hereinafter described,
followed by ester hydrolysis and amide formation by procedures described
elsewhere and well known to those skilled in the art;

##STR00012##

[0510]or [0511](c) reaction of a compound of Formula (VIII) with a
compound of Formula (IX)

##STR00013##

[0511]wherein X.sup.3 is a leaving group or an organometallic reagent and
X.sup.4 is a hydroxyl group or X.sup.3 is a hydroxyl group and X.sup.4 is
a leaving group or an organometallic reagent, and wherein R.sup.1 is
hydroxymethyl or a protected version thereof;process (c) could also be
accomplished using the intermediate ester Formula (X).sub.7 followed by
ester hydrolysis and amide formation by procedures described elsewhere
and well known to those skilled in the art;

##STR00014##

[0512]or [0513](d) reaction of a compound of Formula (XI) with a compound
of Formula (XII),

##STR00015##

[0513]wherein X.sup.5 is a leaving group; and wherein R.sup.1 is
hydroxymethyl or a protected version thereof;and thereafter, if
necessary:i) converting a compound of Formula (I) into another compound
of Formula (I);ii) removing any protecting groups; and/oriii) forming a
salt, pro-drug or solvate thereof.

[0514]Suitable leaving groups X.sup.1 to X.sup.5 for processes b) to d)
are any leaving group known in the art for these types of reactions, for
example halo, alkoxy, trifluoromethanesulfonyloxy, methanesulfonyloxy, or
p-toluenesulfonyloxy; or a group (such as a hydroxy group) that may be
converted into a leaving group (such as an oxytriphenylphosphonium group)
in situ.

[0515]Suitable values for R.sup.1 as a protected hydroxy group are any
suitable protected hydroxy group known in the art, for example simple
ethers such as a methyl ether, or silylethers such as
--OSi[(1-4C)alkyl].sub.3 (wherein each (1-4C)alkyl group is independently
selected from methyl, ethyl, propyl, isopropyl, and tertbutyl). Examples
of such trialkylsilyl groups are trimethylsilyl, triethylsilyl,
triisopropylsilyl and tert-butyldimethylsilyl. Further suitable silyl
ethers are those containing phenyl and substituted phenyl groups, such as
--Si(PhMe.sub.2) and --Si(TolMe.sub.2) (wherein Tol=methylbenzene).
Further suitable values for hydroxy protecting groups are given
hereinafter.

[0516]Compounds of Formulae (III) to (XII) are commercially available, or
are known in the art, or may be made by processes known in the art, for
example as shown in the accompanying Examples. For further information on
processes for making such compounds, we refer to our PCT publications WO
03/000267, WO 03/015774 and WO 03/000262 and references therein. In
general it will be appreciated that any aryl-O or alkyl-O bond may be
formed by nucleophilic substitution or metal catalysed processes,
optionally in the presence of a suitable base.

[0517]Examples of conversions of a compound of Formula (I) into another
compound of Formula (I), well known to those skilled in the art, include
functional group interconversions such as hydrolysis, hydrogenation,
hydrogenolysis, oxidation or reduction, and/or further functionalisation
by standard reactions such as amide or metal-catalysed coupling, or
nucleophilic displacement reactions. An example would be removal of an
R.sup.3=chloro substituent, for example by reaction with hydrogen at
atmospheric or elevated pressure, in a suitable solvent such as
THF/methanol or ethanol.

[0518]Specific reaction conditions for the above reactions are as follows,
wherein when P.sup.1 is a protecting group P.sup.1 is preferably
(1-4C)alkyl, for example methyl or ethyl:

Process a)--coupling reactions of amino groups with carboxylic acids to
form an amide are well known in the art. For example,(i) using an
appropriate coupling reaction, such as a carbodiimide coupling reaction
performed with EDAC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride) in the presence of dimethylaminopyridine (DMAP) in a
suitable solvent such as dichloromethane (DCM), chloroform or
dimethylformamide (DMF) at room temperature; or(ii) reaction in which the
carboxylic group is activated to an acid chloride by reaction with oxalyl
chloride in the presence of a suitable solvent such as DCM. The acid
chloride can then be reacted with a compound of Formula (IV) in the
presence of a base, such as triethylamine or pyridine, in a suitable
solvent such as chloroform or DCM at a temperature between 0.degree. C.
and 80.degree. C.Process b)--compounds of Formula (V) and (VI) can be
reacted together in a suitable solvent, such as DMF or tetrahydrofuran
(THF), with a base such as sodium hydride or potassium tert-butoxide, at
a temperature in the range 0 to 200.degree. C., optionally using
microwave heating or metal catalysis such as palladium(II)acetate,
palladium on carbon, copper(II)acetate or copper(I)iodide; alternatively,
compounds of Formula (V) and (VI) can be reacted together in a suitable
solvent, such as THF or DCM, with a suitable phosphine such as
triphenylphosphine, and azodicarboxylate such as diethylazodicarboxylate;
process b) could also be carried out using a precursor to the ester of
formula (VII) such as an aryl-nitrile or trifluoromethyl derivative,
followed by conversion to a carboxylic acid and amide formation as
previously described;Process c)--compounds of Formula (VIII) and (IX) can
be reacted together in a suitable solvent, such as DMF or THF, with a
base such as sodium hydride or potassium tert-butoxide, at a temperature
in the range 0 to 200.degree. C., optionally using microwave heating or
metal catalysis such as palladium(II)acetate, palladium on carbon,
copper(II)acetate or copper(I)iodide; process c) could also be carried
out using a precursor to the ester of formula (X) such as an aryl-nitrile
or trifluoromethyl derivative, followed by conversion to a carboxylic
acid and amide formation as previously described;Process d)--reaction of
a compound of Formula (XI) with a compound of Formula (XII) can be
performed in a polar solvent, such as DMF or a non-polar solvent such as
THF with a strong base, such as sodium hydride or potassium tert-butoxide
at a temperature between 0 and 200.degree. C., optionally using microwave
heating or metal catalysis, such as palladium(II)acetate, palladium on
carbon, copper(II)acetate or copper(I)iodide.

[0519]Certain intermediates of formula (III), (VI), (VII), (IX) and; or
(XI) are believed to be novel and comprise an independent aspect of the
invention.

[0520]Certain intermediates of formula (III), (IX) and, or (XI) wherein
R.sup.1 is hydroxymethyl, methoxymethyl or a trialkylsilylether are
believed to be novel and comprise an independent aspect of the invention.

[0521]During the preparation process, it may be advantageous to use a
protecting group for a functional group within the molecule. Protecting
groups may be removed by any convenient method as described in the
literature or known to the skilled chemist as appropriate for the removal
of the protecting group in question, such methods being chosen so as to
effect removal of the protecting group with minimum disturbance of groups
elsewhere in the molecule.

[0522]Specific examples of protecting groups are given below for the sake
of convenience, in which "lower" signifies that the group to which it is
applied preferably has 1-4 carbon atoms. It will be understood that these
examples are not exhaustive. Where specific examples of methods for the
removal of protecting groups are given below these are similarly not
exhaustive. The use of protecting groups and methods of deprotection not
specifically mentioned is of course within the scope of the invention.

[0527]Methods appropriate for removal of hydroxy and amino protecting
groups include, for example, nucleophilic displacement, acid-, base,
metal- or enzymically-catalysed hydrolysis, catalytic
hydrogenolysis/hydrogenation or photolytically for groups such as
o-nitrobenzyloxycarbonyl, or with fluoride ions for silyl groups. For
example, methylether protecting groups for hydroxy groups may be removed
by trimethylsilyliodide. A tert-butyl ether protecting group for a
hydroxy group may be removed by hydrolysis, for example by use of
hydrochloric acid in methanol.

[0529]Aralkoxymethyl, groups may be introduced onto the amide group by
reacting the latter group with the appropriate aralkoxymethyl chloride,
and removed by catalytic hydrogenation. Alkoxymethyl, tri alkyl/arylsilyl
and tri alkyl/silyloxymethyl groups may be introduced by reacting the
amide with the appropriate chloride and removing with acid; or in the
case of the silyl containing groups, fluoride ions. The alkoxyphenyl and
alkoxybenzyl groups are conveniently introduced by arylation or
alkylation with an appropriate halide and removed by oxidation with ceric
ammonium nitrate. Finally alk-1-enyl groups may be introduced by reacting
the amide with the appropriate aldehyde and removed with acid.

[0530]The following examples are for illustration purposes and are not
intended to limit the scope of this application. Each exemplified
compound represents a particular and independent aspect of the invention.
In the following non-limiting Examples, unless otherwise stated:
[0531](i) evaporations were carried out by rotary evaporation in vacuo
and work-up procedures were carried out after removal of residual solids
such as drying agents by filtration; [0532](ii) operations were carried
out at room temperature, that is in the range 18-25.degree. C. and under
an atmosphere of an inert gas such as argon or nitrogen; [0533](iii)
yields are given for illustration only and are not necessarily the
maximum attainable, [0534](iv) the structures of the end-products of the
Formula (I) were confirmed by nuclear (generally proton) magnetic
resonance (NMR) with a field strength (for proton) of 300 MHz (generally
using a Varian Gemini 2000) or 400 MHz (generally using a Bruker Avance
DPX400), unless otherwise stated, and mass spectral techniques; proton
magnetic resonance chemical shift values were measured on the delta scale
and peak multiplicities are shown as follows: s, singlet; d, doublet; t,
triplet; m, multiplet; br, broad; q, quartet, quin, quintet; [0535](v)
intermediates were not generally fully characterised and purity was
assessed by thin layer chromatography (TLC), high-performance liquid
chromatography (HPLC), infra-red (IR) or NMR analysis; [0536](vi)
Purification by chromatography generally refers to flash column
chromatography, on silica unless otherwise stated. Column chromatography
was generally carried out using prepacked silica cartridges (from 4 g up
to 400 g) such as Redisep.TM. (available, for example, from Presearch
Ltd, Hitchin, Herts, UK) or Biotage (Biotage UK Ltd, Hertford, Herts,
UK), eluted using a pump and fraction collector system; [0537](vii) Mass
spectra (MS) data % was generated on an LCMS system where the HPLC
component comprised generally either a Agilent 1100 or Waters Alliance HT
(2790 & 2795) equipment and was rum on a Phemonenex Gemini C18 5 .mu.min
50.times.2 mm column (or similar) eluting with either acidic eluent (for
example, using a gradient between 0-95% water/acetonitrile with 5% of a
1% formic acid in 50:50 water:acetonitrile (v/v) mixture; or using an
equivalent solvent system with methanol instead of acetonitrile), or
basic eluent (for example, using a gradient between 0-95% water
acetonitrile with 5% of a 0.1% 880 Ammonia in acetonitrile mixture); and
the MS component comprised generally a Waters ZQ spectrometer.
Chromatograms for Electrospray (ESI) positive and negative Base Peak
Intensity, and UV Total Absorption Chromatogram from 220-300 nm are
generated and values for m/z are given; generally, only ions which
indicate the parent mass are reported and unless otherwise stated the
value quoted is (M-H).sup.-; [0538](viii) Suitable microwave reactors
include "Smith Creator", "CEM Explorer", "Biotage Initiator sixty" and
"Biotage Initator eight".

[0560]Tetra-n-butyl ammonium fluoride (1.0M in THF, 0.832 mL, 0.832 mmol)
was added to a solution of
3-((1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsu-
lfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide (425 mg, 0.756 mmol) in THF (5
mL) and the reaction stirred for 1.5 h. A further portion of
tetra-n-butyl ammonium fluoride (0.83 mL) in THF was added and the
reaction was stirred for a further 1.5 h. The reaction was then diluted
with diethyl ether (40 mL) and 1M aqueous hydrochloric acid (20 mL) and
the aqueous layer was re-extracted with diethyl ether (20 mL). The
combined organic layers were dried (MgSO.sub.4), filtered and evaporated.
Purification by column chromatography, eluting with 50% to 100% ethyl
acetate in hexanes, afforded the title compound as a foam (200 mg, 60%).

[0566]Lithium hydroxide monohydrate (346 mg, 8.24 mmol) was added to a
solution of methyl
3-((1S)-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulf-
onyl)phenoxy]benzoate (3.70 g, 7.49 mmol) in THF (50 mL) and water (10 mL)
and the reaction stirred for 2 h. A further portion of lithium hydroxide
monohydrate (346 mg, 8.24 mmol) was then added and the reaction was
heated at 45.degree. C. for 1.5 h. The THF was then evaporated and water
layer was extracted with diethyl ether (10 mL). The remaining aqueous
layer was acidified with 5% w/v aqueous citric acid and extracted
(2.times.50 mL) with ethyl acetate and the combined organic layers were
dried (MgSO.sub.4), filtered and evaporated to afford the title compound
as a gum (2.54 g, 71%).

[0572]Methyl 3-(phenylmethyl)oxy-5-[4-(methylsulfonyl)phenoxy]benzoate
(3.50 g, 8.50 mmol) was dissolved in THF (60 mL) followed by 10%
palladium on carbon (500 mg). The reaction was then placed under a
hydrogen atmosphere by an evacuation-backfill technique. The reaction was
then stirred vigorously for 4 h followed by filtration and evaporation
which afforded the title compound as an colourless oil (2.75 g, 100%).

[0575]Potassium carbonate (3.21 g, 23.2 mmol) was added to a solution of
methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (3.00 g, 11.6 mmol) in DMF
(30 mL) followed by addition of 1-fluoro-4-(methylsulfonyl)benzene (2.02
g, 11.6 mmol) and the reaction was heated at 120.degree. C. for 3 h. The
solvent was then removed in vacuo and the residue was taken up in
saturated aqueous sodium hydrogencarbonate (50 mL) and ethyl acetate (150
mL). The organic layer was separated, washed with 1M aqueous hydrochloric
acid (50 mL) then dried (MgSO.sub.4), filtered and evaporated.
Purification by column chromatography, eluting with 1:4 to 1:1 ethyl
acetate:hexanes, afforded the title compound as a colourless oil (3.50 g,
73%).

[0581]tert-Butyl(dimethyl)silyl chloride (5.90, 39.5 mmol) was added to a
solution of (2R)-propane-1,2-diol (3.00 g, 39.5 mmol) in DCM (100 mL)
followed by diisopropylethylamine (7.10 g, 55.3 mmol) and the reaction
was stirred under argon for 72 h. The reaction was diluted with diethyl
ether (500 mL) and water (140 mL) and the organic layer was separated
then dried (MgSO.sub.4), filtered and evaporated. Purification by column
chromatography, eluting with 1:15 to 1:10 ethyl acetate:hexane, afforded
the title compound as a colourless oil (6.00 g, 80%).

[0585]TFA (2 mL) was added to a solution of
3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-[4-(methoxym-
ethyl)-1,3-thiazol-2-yl]-5-[4-(methylsulfonyl)phenoxy]benzamide (325 mg,
0.536 mmol) in DCM (4 mL) and water (1 mL) and the reaction was stirred
for 1 h. The reaction was basified to pH7-8 with saturated aqueous sodium
hydrogencarbonate and then extracted with DCM (2.times.20 mL). The
combined organic layers were dried (MgSO.sub.4), filtered and evaporated
and purified by column chromatography, eluting with 50% to 100% ethyl
acetate in hexanes, to afford the title compound as a white foam (147 mg,
56%).

[0595]Sodium hexamethyldisilazide (1.0M in THF, 0.67 mL, 0.67 mmol) was
added to a solution of 4-(chloromethyl)-1,3-thiazol-2-amine (J. Indian
Chem. Soc. 1960, 37, 241; 100 mg, 0.67 mmol) in methanol (5 mL) followed
by stirring under argon at ambient temperature for 72 h. The solvent was
then removed under reduced pressure and the residue was taken up in
saturated aqueous sodium hydrogencarbonate (20 mL) and ethyl acetate (50
mL). The organic layer was separated then dried (MgSO.sub.4), filtered
and evaporated. Purification by column chromatography, eluting with 80%
to 100% ethyl acetate in hexanes, afforded the title compound as a
colourless oil (20 mg, 21%).

[0599]5-Methyl-1H-pyrazol-3-amine (800 mg, 8.25 mmol) was dissolved in DMF
(10 mL) at 0.degree. C. and treated with sodium hydride (336 mg, 8.25
mmol) followed by stirring for a further 30 min. Warmed di-tert-butyl
dicarbonate (1.80 g, 8.25 mmol) was then slowly added via syringe over 5
min and the reaction was allowed to warm to RT and stirred for a further
1 h. The reaction was taken up in saturated aqueous sodium
hydrogencarbonate (50 mL) and ethyl acetate (100 mL). The organic layer
was separated then dried (MgSO.sub.4), filtered and evaporated.
Purification by column chromatography, eluting with 50% to 100% ethyl
acetate in hexanes, afforded the title compound as a colourless oil (380
mg, 23%).

[0602]Trimethylsilyl iodide (11.1 mL, 76.3 mmol) was added to a solution
of 3-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(m-
ethylsulfonyl)phenoxy]benzamide (7.00 g, 15.3 mmol) in dry acetonitrile
(100 mL) under argon for 21 h. Water (40 mL) was added to quench the
reaction and the acetonitrile was removed in vacuo. The residue was
diluted with ethyl acetate (200 mL) and 1M aqueous hydrochloric acid. The
organic layer was separated and further washed with 10% w/v aqueous
sodium thiosulfate pentahydrate to remove residual iodine. The organic
layer was separated, dried (MgSO.sub.4), filtered and evaporated and
purified by column chromatography, eluting with 3% to 5% methanol in DCM,
to give the title compound as a white foam (5.70 g, 84%).
Recrystallisation from hot ethanol (125 mg/mL) afforded the title
compound as colourless needles (87% recovery). Mpt 126-132.degree. C.

[0606]DIPEA (2.5 equivalents) was added to a suspension of
3-{(1S)-2-methoxy-(1-methylethyl)oxy}-5-{[4-(methylsulfonyl)phenyl]oxy}be-
nzoic acid (1 equivalent), HATU (1.25 equivalents) and the appropriate
amine (1.25 equivalents) in DMF (20 mL). The initial suspension dissolved
into a dark orange solution. The resulting mixture was stirred at ambient
temperature for 2 hours. The DMF was removed in vacuo, and the residue
azeotroped with toluene. Water was added and the mixture extracted with
ethyl acetate. The extracts were combined and washed sequentially with 1M
hydrochloric acid, saturated sodium hydrogen carbonate solution and
brine. The solution was dried (MgSO.sub.4), filtered, and evaporated in
vacuo to give the crude product which was chromatographed (50% ethyl
acetate in isohexane) to give desired compound (40-70% yield).

[0608]A solution of methyl
3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[4-(methylsulfonyl)phenyl]oxy}be-
nzoate (60.9 mmol) in THF (400 mL) was treated with a solution of 1M
sodium hydroxide (125 mmol), and the reaction mixture stirred for 13
hours at ambient temperature. Most of the organic solvent was removed in
vacuo, and the remaining solution was diluted with water (150 mL). The
resulting aqueous solution was acidified to pH4 with 1M citric acid
solution, and extracted with ethyl acetate (2.times.100 mL). The extracts
were combined, washed with brine, dried (MgSO.sub.4), and evaporated to
give the desired compound (83% yield).

[0614]Methyl
3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoate (50.0
g, 0.152 mmol) was dissolved in a mixture of THF:ethanol (600 mL) and the
flask evacuated and purged with nitrogen (3 times). 10% Palladium on
carbon (5.0 g) was added and the flask further evacuated and finally
purged with hydrogen gas. The reaction mixture was stirred at ambient
temperature for 20 hours until completion. The reaction mixture was
evacuated and purged with nitrogen (3 times). The catalyst was filtered
off, and the filtrate concentrated in vacuo to give the desired compound
(36.7 g).

[0617]To a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate
(77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7 g
of 3 mmol/g loading, 155 mmol) and (R)-(-)-1-methoxy-2-propanol (102
mmol). The stirred solution was blanketed with argon and cooled in an ice
bath. A solution of DIAD (116 mmol) was added dropwise by syringe over 10
minutes. The solution was stirred for 20 minutes and filtered, washing
the residue with THF (500 mL). The filtrate and washings were combined,
and evaporated to give the desired compound which was used without
further purification.

[0622]TFA (0.5 mL) was added to a solution of tert-butyl
3-({3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]benzoy-
l}amino)-1H-pyrazole-1-carboxylate (180 mg, 0.330 mmol) in dry DCM (3 mL)
and the reaction was stirred under argon for 3 h. A further portion of
TFA (0.2 mL) was then added and the reaction was stirred for 30 min
before all the solvent was removed in vacuo. The residue was taken up in
ethyl acetate (30 mL) and saturated aqueous sodium hydrogencarbonate (15
mL) and the residue was evaporated then re-evaporated with DCM/hexanes to
produce the title compound as a colourless foam (145 mg, 100%).

[0628]1H-Pyrazol-3-amine (428 mg, 5.15 mmol) was dissolved in DMF (5 mL)
at 0.degree. C. and treated with sodium hydride (206 mg, 5.15 mmol)
followed by stirring for a further 30 min. Warmed di-tert-butyl
dicarbonate (1.12 g, 5.15 mmol) was then slowly added via syringe over 5
min and the reaction was allowed to warm to RT and stirred for a further
2 h. The reaction was taken up in saturated aqueous sodium
hydrogencarbonate (50 mL) and ethyl acetate (100 mL). The organic layer
was separated then dried (MgSO.sub.4), filtered and evaporated.
Purification by column chromatography (eluting with 1:1 ethyl
acetate:hexanes to neat ethyl acetate) afforded the title compound as a
white solid (117 mg, 18%).

[0635]Methyl
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methyle-
thoxy]benzoate (100 mg, 0.25 mmol) was dissolved in THF (2.0 mL and water
(0.2 mL) and solid lithium hydroxide (21 mg, 0.5 mmol) added. The
resultant mixture was stirred at ambient temperature for 16 hours. Water
(10 mL) was added and the mixture partially reduced in vacuo and then
extracted with ethyl acetate. The aqueous liquors were acidified with 1M
hydrochloric acid and re-extracted with ethyl acetate (2.times.10 mL).
The extracts were combined, washed with brine, dried (MgSO.sub.4),
filtered, and evaporated in vacuo to give the crude product which was
used without further purification (70 mg).

[0638]To a portion of methyl
3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-hydroxybenzo-
ate (102 mg, 0.3 mmol) and 1-(3,4-difluorobenzoyl)azetidine (71 mg, 0.36
mmol) in DMF (2.0 mL) was added potassium carbonate (207 mg, 1.5 mmol)
and the stirred mixture heated at 160.degree. C. in a `Smith Creator
Microwave` for 120 minutes. The mixture was allowed to reach ambient
temperature and pressure then partitioned between ethyl acetate
(2.times.25 mL) and water (25 mL). The organic layer was separated,
washed with brine, dried (MgSO.sub.4), and evaporated in vacuo to give
the crude product which was used without further purification (100 mg).

[0644](2R)-1-{[tert-Butyl(dimethyl)silyl]oxy}propan-2-ol (3.31 g, 17.4
mmol) was added to a solution of methyl
3-hydroxy-5-{[phenylmethyl]oxy}benzoate (3.00 g, 11.6 mmol) in THF (50
mL) at 0.degree. C. followed by addition of triphenylphosphine (4.57 g,
17.4 mmol) then DIAD (3.43 mL, 17.4 mmol) and the reaction was warmed to
RT and stirred for 16 h. The reaction was quenched with water (100 mL)
and diethyl ether (400 mL) and the organic layer was separated then dried
(MgSO.sub.4) and evaporated. Purification by column chromatography,
eluting with 1:15 to 1:5 ethyl acetate:hexane, afforded the title
compound as a colourless oil (4.00 g, 80%).

[0651]3-((1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-(phen-
ylmethyl) oxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (1.8 g, 3.64 mmol) was
dissolved in methanol (50 mL) and the flask evacuated and purged with
nitrogen (3 times). 10% Palladium on carbon (0.2 g) was added and the
flask further evacuated and finally purged with hydrogen gas. The
reaction mixture was stirred at ambient temperature for 16 hours until
completion. The reaction mixture was evacuated and purged with nitro-en
(3 times). The catalyst was filtered off, and the filtrate concentrated
in vacuo to give the desired compound (1.45 g).

[0654]DIPEA (4.06 g, 23.4 mmol) was added to a suspension of
3-{(phenylmethyl)oxy}-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-
ethoxy)benzoic acid (2.43 g, 5.84 mmol), 1-methyl-1H-pyrazole-3-amine
(0.85 g, 8.76 mmol) and HATU (4.66 g, 12.3 mmol) in DMF (50 mL) and
stirred at ambient temperature for 16 hours. The resultant mixture was
partially reduced in vacuo, poured onto water (100 mL) and extracted with
diethyl ether (2.times.50 mL). The extracts were washed with water and
brine then dried (MgSO.sub.4), filtered and reduced to an opaque gum
which partially crystallized. The crude product was purified by column
chromatography, eluting with 0-100% ethyl acetate in isohexane, to give
the title compound as a colourless oil (1.87 g).

[0657]Methyl
3-((s)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-[(phenylmethy-
l)oxy]benzoate (3.0 g, 6.98 mmol) was dissolved in THF (50 mL) and water
(10 mL) and lithium hydroxide monohydrate (586 mg, 13.95 mmol) added. The
resultant mixture was heated with stirring at 45.degree. C. for 2 hours,
then at ambient temperature for 16 hours, and at 45.degree. C. for a
further 4 hours. Water (40 mL) was added and the solvent removed in
vacuo. The resultant solution was acidified carefully with 1M citric acid
(2 equivalents), washed with water and brine then dried (MgSO.sub.4),
filtered and evaporated in vacuo to give the title compound as a
colourless gum (2.58 g).

[0664]The required amides for the synthesis of Examples 6 and 6a were
prepared from 3-chloro-4-fluorobenzoic acid as follows:

1-(3-Chloro-4-fluorobenzoyl)azetidine

##STR00057##

[0666]To a solution of 3-chloro-4-fluorobenzoic acid (1.74 g, 10.0 mmol)
in DCM (50 mL) was added oxalyl chloride (1.05 mL, 12.0 mmol) and DMF (1
drop). The mixture was stirred at ambient temperature for 16 hours and
the DCM and excess oxalyl chloride evaporated in vacuo. The residual acid
chloride and azetidine hydrochloride (1.12 g, 12 mmol) were taken up in
DCM (25 mL) and triethylamine (4.18 mL, 30 mmol) added to the mixture,
which was stirred at ambient temperature for 2 hours. The DCM was
evaporated in vacuo, and the residue partitioned between ethyl acetate
(100 mL) and 1N hydrochloric acid (50 mL). The ethyl acetate layer was
washed sequentially with saturated aqueous sodium hydrogen carbonate and
brine, dried (MgSO.sub.4), and evaporated. The residue was crystallized
from ethyl acetate/isohexane to give the title compound (1.64 g).

[0673]The material can be crystallised from an ethylacetate and toluene
mixture after purification by chromatography (on silica and then/or on
neutral alumina) and, where necessary, treatment with activated charcoal;
mpt 131.degree. C.

[0674]In a similar manner, Reference Example 7a was prepared from
3-chloro-4-[(3-{[(1S)-2-hydroxy-1-methylethyl]oxy}-5-{[(1-methyl-1H-pyraz-
ol-3-yl)amino]carbonyl}Phenyl)oxy]-N,N-dimethylbenzamide:

[0677]Potassium carbonate (182 mg, 1.32 mmol) was added to a mixture of
3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)b-
enzamide (200 mg, 0.66 mmol) and 1-(3,4-difluorobenzoyl)azetidine (137 mg,
0.69 mmol) in acetonitrile (5.0 mL) and the stirred mixture heated at
160.degree. C. in a `Smith Creator Microwave` for 4 hours. The mixture
was allowed to reach ambient temperature and pressure and reduced in
vacuo. The residual oil was partitioned between ethyl acetate (50 mL) and
water (50 mL). The ethyl acetate layer was separated, washed with brine,
dried (MgSO.sub.4), and evaporated to a residue which was chromatographed
on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane,
to give the desired compound (34 mg).

[0681]Trimethylsilyl iodide (6.06 mL, 42.75 mmol) was added to a solution
of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-
-2-yl)benzamide (2.71 g, 8.55 mmol) in dry acetonitrile (150 mL) and
stirred for 24 h. Methanol (30 mL) was added to quench the reaction and
stirred for 10 mins. 10% w/v Aqueous sodium thiosulfate pentahydrate (20
mL) was added to the mixture and the organic solvents removed in vacuo.
The residue was brought to pH5 with 1M hydrochloric acid and ethyl
acetate (80 mL) added. A yellow solid (1.4 g) was separated by
filtration. The aqueous filtrate was reextracted into ethyl acetate
(2.times.80 mL) and the combined organic layers dried (MgSO.sub.4),
filtered and the solvents removed in vacuo. This residue was combined
with the yellow solid obtained above and purified by column
chromatography, eluting with 5% to 10% methanol in DCM, to give the title
compound (1.70 g)

[0684]3-{[(1S)-1-Methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)-5-
-[(phenylmethyl)oxy]benzamide (4.5 g, 11 mmol) was dissolved in ethanol
(35 mL) and THF (35 mL) and the flask evacuated and purged with argon (3
times). 10% Palladium on carbon (0.45 g) was added and the flask further
evacuated and finally purged with hydrogen gas. The reaction mixture was
stirred at ambient temperature for 20 hours until completion. The
reaction mixture was evacuated and purged with nitrogen (3 times). The
catalyst was filtered off through celite, and the filtrate concentrated
in vacuo to give the desired compound (3.21 g).

[0689]The aryl fluoride used to prepare Example 8 was prepared as
described below:

1-(3,4-Difluorobenzyl)azetidine

##STR00066##

[0691]Oxalyl chloride (1.05 mL, 12.0 mmol) was added to a solution of
3,4-difluorobenzoic acid (1.58 g, 10 mmol) in DCM (50 mL) containing DMF
(1 drop). The reaction was stirred at ambient temperature for 16 h then
evaporated to dryness. The residue was redissolved in DCM (25 mL) and
azetidine hydrochloride (1.12 g, 12.0 mmol) added followed by
triethylamine (4.18 mL, 30.0 mmol). The mixture was stirred at ambient
temperature for 2 h then concentrated in vacuo. The residue was
partitioned between ethyl acetate and 1N hydrochloric acid, the organic
phase washed with a saturated aqueous solution of sodium bicarbonate
followed by brine, dried (MgSO.sub.4), and concentrated in vacuo. The
title compound was crystallized from an ethyl acetate; hexane mixture to
give a white crystalline solid (1.0 g).

[0696]1-Chloro-N,N,2-trimethyl-1-propenylamine (0.86 g, 6.56 mmol) was
added to a solution of
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dime-
thyl)silyl]oxy}-1-methylethoxy)benzoic acid (3 g, 5.96 mmol) in DCM (100
mL) and stirred at RT for 1 hour. 2-Amino-5-methylpyrazine (1.3 g, 11.9
mmol) and pyridine (0.94 mL, 11.9 mmol) were added and the reaction
stirred for a further 30 mins. The solvent was removed in vacuo. Water
(100 mL) was added and the mixture extracted with ethyl acetate
(3.times.50 mL). The extracts were combined and washed with water (100
mL), brine (100 mL), dried (MgSO.sub.4), filtered, and evaporated in
vacuo to give the crude product which was chromatographed on silica,
eluting with a gradient of 50-100% ethyl acetate in isohexane, to give
the desired compound (3.6 g).

[0707]The preparation of methyl
3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate was described in
Example 3.

[0708]An analogous procedure can be employed in the preparation of Example
8a from 3-[4-(azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tert-bu-
tyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-(5-methylpyrazin-2-yl)benzamide.
The desired product can then be isolated following purification on
silica, eluting with 5% methanol in ethyl acetate, and crystallization
from ethyl acetate/isohexane, mpt 133.degree. C.

[0709]3-[4-(Azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tert-butyl-
(dimethyl)silyl]oxy}-1-methylethoxy)-N-(5-methylpyrazin-2-yl)benzamide was
prepared from methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate
in an analogous fashion to
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dime-
thyl)silyl]oxy}-1-methylethoxy)-N-(5-methylpyrazin-2-yl)benzamide but
replacing 1-(3,4-difluorobenzoyl)azetidine with
t-(3-chloro-4-fluorobenzoyl)azetidine.

[0713]The sample was dissolved in ethyl acetate, the vial containing this
solution was allowed to stand inside another sealed vial containing
toluene until crystals formed. The crystals were filtered and washed with
toluene and then iso-hexane. Mpt 124.degree. C.

[0715]The following compounds were made in an analogous fashion from
3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-
-(1-ethyl-1H-pyrazol-3-yl)-5-hydroxybenzamide and the appropriate aryl
fluoride.

[0717]A solution of
3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-
-(1-ethyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (2.40 g, 4.71
mmol) and THF (80 mL) was evacuated and purged with Argon (.times.3).
Palladium on carbon (10%, 422 mg) was added and reaction mixture was
evacuated and finally purged with hydrogen gas. Reaction mixture was left
to stir at ambient temperature under hydrogen for 16 hours. Pd/C was
filtered off and concentrated in vacuo to give the product as a
colourless oil (1.87 g, 95%).

[0722]The aryl fluorides used in the preparation of Examples 9, 9a and 9c
were described in previous examples. The aryl fluoride used in the
preparation of Example 9b was prepared as described below:

3,4-Difluorophenyl Ethyl Sulfone

##STR00083##

[0724]To a solution of 4-ethylsulphanyl-1,2-difluorobenzene (1.50 g) in
DCM (50 mL) was added 75% m-chloroperbenzoic acid (2.97 g) and the
mixture stirred at ambient temperature for 16 h. The mixture was washed
successively with saturated potassium carbonate (20 mL) and brine (30 mL)
then dried with magnesium sulphate, filtered and reduced in vacuo. The
resultant clear oil was chromatographed on silica, eluting with 0-50%
ethyl acetate in isohexane, and the faster running product isolated (0.90
g). The required 3,4-difluorophenyl ethyl sulfone was used without
further characterisation.

[0725]The aryl fluorides used in the preparation of Examples 9d-e were
prepared in an analogous manner to 1-(3,4-difluorobenzoyl)azetidine
described in Example 8 using the appropriate amine.

[0731]A solution of
3-{[4-(azetidin-1-ylcarbonyl)-2-chlorophenyl]oxy}-N-(1-ethyl-1H-pyrazol-3-
-yl)-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzamide (246 mg, 0.504 mmol)
and triethylamine (0.42 mL, 3.02 mmol) in THF (6 mL) and methanol (6 mL)
was evacuated and purged with argon (.times.3). Palladium on carbon (10%
w/w, 52 mg) was added and reaction mixture was evacuated and finally
filled with hydrogen gas. The reaction mixture was left to stir at
ambient temperature under hydrogen for 2 hours. The Pd/C was filtered off
and mixture partitioned between ethyl acetate and 1M hydrochloric acid
solution. The organic phase was dried (MgSO.sub.4) and the filtrate
concentrated in vacuo to give the product (170 mg, 73%).

[0737]In a similar manner to that described above, the following compound
was also prepared from
3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N--
(1-methyl-1H-pyrazol-3-yl)benzamide and the appropriate boronic acid:--

[0739]Potassium carbonate (276 mg) was added to a solution of
3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3--
yl)benzamide (291 mg) and 3,4-difluoro-N,N-dimethylbenzamide (204 mg) in
acetonitrile (3-5 mL) and the stirred mixture heated at 160.degree. C. in
a `Smith Creator Microwave` for 15 h. The mixture was allowed to return
to ambient temperature and pressure, the acetonitrile evaporated, and the
residue chromatographed on silica, eluting with 0-5% methanol in ethyl
acetate, to give the desired compound (63 mg).

[0743]To a solution of 3-hydroxy-5-[(1S)-2-methoxy-(1
methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (10.0 g) in
acetonitrile (200 mL) under an atmosphere of argon, was added
iodotrimethylsilane (23.8 mL) and the resultant mixture stirred for 16
hours. Methanol (30 mL) was then added and the mixture stirred for 15
minutes, saturated potassium carbonate (30 mL) and sodium thiosulphate
(0.5 g) were then added and the mixture stirred for 2 hours. The
acetonitrile was removed in vacuo, the residue dissolved in water (150
mL) and continuously extracted with ethyl acetate for 16 hours. The ethyl
acetate was removed in vacuo and the residue chromatographed on silica
(eluting with 0-5% methanol in ethyl acetate) to give the desired
compound (7.1 g).

[0746]To a solution of
3-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[(ph-
enylmethyl)oxy]benzamide (7.07 g) in THF (50 mL) and methanol (50 mL) was
added 10% palladium on carbon (727 mg) as a slurry in THF (1 mL) and
methanol (1 mL). The mixture was placed under vacuum and stirred under an
atmosphere of hydrogen for 70 hours. The mixture was filtered through
diatomaceous earth, and the diatomaceous earth washed with methanol
(2.times.100 mL), followed by evaporation in vacuo. The residues were
dissolved in ethyl acetate (10 mL), treated with isohexane (40 mL), the
solid filtered off and washed with isohexane (50 mL) to afford the
desired compound (5.17 g) which was used without further purification.

[0749]A solution of
3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid
(8.73 g) in DCM (150 mL) was cooled to 0.degree. C. Oxalyl chloride (4.81
mL) and DMF (0.15 mL) were slowly added with stirring. The mixture was
allowed to warm to ambient temperature and stirred for 16 hours,
following which the organics were removed in vacuo, and the residues
azeotroped with toluene (75 mL). The crude material was dissolved in DCM
(75 mL) and slowly added to a stirred suspension of
1-methyl-1H-pyrazol-3-amine (3.35 g) and DIPEA (14.4 mL) in DCM (75 mL).
The mixture was stirred at ambient temperature for 18 hours, before the
organics were evaporated in vacuo and the residue dissolved in ethyl
acetate (150 mL). The organics were washed with 1M aqueous hydrochloric
acid (100 mL) and brine (50 mL), and dried (MgSO.sub.4), before
evaporation in vacuo to give crude material. This was chromatographed on
a 200 g Biotage Flash 75 SiO.sub.2 column (eluting with 30 to 90% ethyl
acetate in isohexane), and evaporated in vacuo to afford the desired
compound (7.07 g).

[0752]A solution of methyl
3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoate (77.4
mmol) in a mixture of THF (232 mL) and methanol (232 mL) was treated with
a solution of 2M sodium hydroxide (232 mmol), and the reaction mixture
stirred for 4 hours at ambient temperature. The resulting solution was
diluted with water (250 mL) and most of the organic solvent removed in
vacuo. The resulting suspension was washed with diethyl ether
(3.times.200 mL) and the organic washings discarded. The resulting
aqueous solution was acidified to pH4 with 2M hydrochloric acid solution
and extracted with ethyl acetate (2.times.200 mL). The extracts were
combined, washed with brine, dried (MgSO.sub.4), and evaporated to give
the desired compound (99% yield).

[0755]To a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate
(77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7 g
of 3 mmol/g loading, 155 mmol) and (R)-(-)-1-methoxy-2-propanol (102
mmol). The stirred solution was blanketed with argon and cooled in an ice
bath. A solution of DIAD (116 mmol) was added dropwise by syringe over 10
minutes. The solution was stirred for 20 minutes and filtered, washing
the residue with THF (500 mL). The filtrate and washings were combined,
and evaporated to give the desired compound which was used without
further purification.

[0760]The aryl fluorides used in the preparation of Examples 12, 12b were
prepared in an analogous fashion to 1-(3,4-difluorobenzoyl)azetidine
described in Example 8 by reaction of the appropriate benzoic acid with
the appropriate amine.

[0770]Potassium carbonate (182 mg, 1.32 mmol) was added to a mixture of
3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-hydroxy-N-(1-
-isopropyl-1H-pyrazol-3-yl)benzamide (350 mg, 0.81 mmol) and
1-(3-Chloro-4-fluorobenzoyl)azetidine (181 mg, 0.85 mmol) in acetonitrile
(5 mL) and the stirred mixture heated at 160.degree. C. in a `Smith
Creator Microwave` for 15 hours. The mixture was allowed to reach ambient
temperature and pressure and reduced in vacuo. The residual oil was
partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl
acetate layer was separated, washed with brine, dried (MgSO.sub.4), and
evaporated to a residue which was chromatographed on silica, eluting with
a gradient of 50-100% ethyl acetate in isohexane, to give the desired
compound (331 mg)

[0774]A solution of
3-(benzyloxy)-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)--
N-(1-isopropyl-1H-pyrazol-3-yl)benzamide (1.97 g 3.77 mmol) and THF (70
mL) was evacuated and purged with Argon (.times.3). Palladium on carbon
(10% w/w, 400 mg) was added and reaction mixture was evacuated and
finally purged with hydrogen gas. Reaction mixture was left to stir at
ambient temperature under hydrogen for 16 hours. Pd/C was filtered off
and concentrated in vacuo to give the product as a colourless oil (1.58
g, 97%).

[0780]2-Chloroacrylonitrile (3.41 mL, 42.59 mmol) was added at RT to a
stirring solution of N-isopropylhydrazine hydrochloride (4.71 g, 42.6
mmol), potassium carbonate (11.8 g, 85.9 mmol) in water (50 mL). The
reaction was warmed to 45.degree. C. for 4 hours before cooling back to
RT. The aqueous layer was then extracted with ethyl acetate (5.times.30
mL) and the combined organic layers were dried (MgSO.sub.4), treated with
activated charcoal, filtered and evaporated. The residue was purified by
chromatography, eluting with 67%-100% ethyl acetate in hexanes, to afford
the title compound (3.08 g, 58%) as a 6:1 mixture of authentic product to
regioisomeric product as an oil. The material was used without further
purification.

[0782]The aryl fluorides used to prepare Example 13, 13a, 13b are
described in previous examples. 4-Fluorophenyl methyl sulphone used in
the preparation of Example 13c is commercially available. The aryl
fluoride used to prepare Example 13d was prepared as described below.

[0786]3-[4-(Azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxy-1-me-
thylethoxy]-N-(1-isopropyl-1H-pyrazol-3-yl)benzamide (0.33 g, 0.644 mmol)
was dissolved in methanol (4 mL) and THF (4 mL) and the flask evacuated
and purged with argon (3 times). 10% Palladium on carbon (0.033 g) was
added and the flask further evacuated and finally purged with hydrogen
gas. The reaction mixture was stirred at ambient temperature for 20
hours. The reaction mixture was evacuated and purged with nitrogen (3
times). The catalyst was filtered off through celite, and the filtrate
concentrated in vacuo. The residue was chromatographed on silica eluting
with a gradient of 0-100% ethyl acetate in isohexane to give the desired
compound (0.15 g);

[0793]To a solution of
3-{2-chloro-4-[(dimethylamino)sulfonyl]phenoxy}-5-[(1S)-2-methoxy-1-methy-
lethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (1.0 g, 1.9 mmol) in
methanol (20 mL) and THF (20 mL) was added triethylamine (1.5 mL) and 10%
palladium on carbon (100 mg). The resulting mixture was stirred under an
atmosphere of hydrogen for 20 hours. The mixture was filtered through
Celite.RTM. and evaporated under reduced pressure. The residue was
dissolved in DCM (100 mL) and washed with 2M hydrochloric acid (100 mL).
The organic phase was separated and the aqueous reextracted with DCM (100
mL). The combined organic extracts were dried (MgSO.sub.4) and evaporated
to afford the title compound (300 mg, 32%).

[0796]To a solution of
3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3--
yl)benzamide (152 mg, 0.50 mmol) in acetonitrile (3.5 mL) was added
potassium carbonate (345 mg, 2.5 mmol) and
3-chloro-4-fluoro-N,N-dimethylbenzenesulfonamide (237 mg, 1.0 mmol) and
the mixture was heated under microwave conditions at 160.degree. C. for 2
hours. The mixtures were filtered and evaporated. The residue was
purified by flash chromatography (eluting with an increasing gradient of
60 to 100% ethyl acetate in isohexane) to afford the title compound (1.8
g, 98%).

[0799]A solution of 2M dimethylamine in THF (5.9 mL, 12 mmol) was diluted
with DCM (25 mL) and cooled to 0.degree. C. DIPEA (2.8 mL) was added,
followed by and 3-chloro-4-fluorobenzenesulfonyl chloride (2.5 g, 11
mmol) in DCM (25 mL). The resulting mixture was allowed to warm to rt and
stirred for 3 hours. Water (5 mL) and 1M hydrochloric acid (16 mL) was
added. The organic phase was separated and evaporated under reduced
pressure to afford the title compound (2.4 g, 94%).

[0802]A suspension of
4-{3-[(1S)-2-hydroxy-1-methylethoxy]-5-[(1H-pyrazol-3-ylamino)carbonyl]ph-
enoxy}benzoic acid (130 mg, 0.327 mmol), HATU (156 mg, 0.41 mmol),
azetidine hydrochloride (38 mg, 0.41 mmol) and DIPEA (0.143 mL; 0.82
mmol) in DMF (2 mL) was stirred at ambient temperature for 16 hours.
Water was added to the reaction mixture and it was extracted into ethyl
acetate (3.times.30 mL). The organic phases were combined, washed with
brine solution and dried (MgSO.sub.4). The filtrate was concentrated in
vacuo and the residue chromatographed, eluting with 0-50% methanol in
DCM, to give a clear oil which gave a foam under high vacuum (65 mg,
46%).

[0806]A solution of ethyl
4-{3-[(1S)-2-hydroxy-1-methylethoxy]-5-[(1H-pyrazol-3-ylamino)carbonyl]ph-
enoxy}benzoate (175 mg, 0.4 mmol) in THF (5 mL) and water (1 mL) was
treated with 1N sodium hydroxide solution (3 mL) and the reaction stirred
at RT for 16 hours. On completion, the solvent was removed in vacuo and
1N citric acid added until pH 3-4. The white precipitate was collected by
filtration and dried in vacuo to give the desired product as a white
solid (138 mg, 85%).

[0809]Trimethylsilyl iodide (0.27 mL) was added dropwise under argon to a
solution of tert-butyl
3-({3-[4-(ethoxycarbonyl)phenoxy]-5-[(1S)-2-methoxy-1-methyl
ethoxy]benzoyl}amino)-1H-pyrazole-1-carboxylate (167 mg, 0.38 mmol) in
acetonitrile (5 mL) and stirred at ambient temperature for 16 hours.
Sodium thiosulfate solution was added to quench the reaction and the
reaction mixture was extracted into ethyl acetate (3.times.25 mL).
Organic phases were combined and dried (MgSO.sub.4) and the filtrate was
concentrated in vacuo to give a clear oil (180 mg), which was not
purified further.

[0823]Potassium carbonate (1.00 g) was added to a solution of
3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-1-methyl-1H-pyrazol-3-y-
l)benzamide (1.41 g) and 1-chloro-4,5-difluoro-2-(methylsulfonyl)benzene
(0.79 g) in NMP (20 mL). The mixture was heated to 115.degree. C. for 3.5
hours and left to cool before being poured into water (300 mL) and
extracted with ethyl acetate (2.times.150 mL). The combined organics were
washed with water, brine and dried (MgSO.sub.4) before evaporation in
vacuo. Chromatography on silica, eluting with 0 to 10% methanol in ethyl
acetate, afforded the desired compound (0.86 g)

[0825]The preparation of
3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3--
yl)benzamide was described in Example 12.

[0826]The preparation of 1-chloro-4,5-difluoro-2-(methylsulfonyl)benzene
is described below:

1-Choro-4,5-difluoro-2-(methylsulfonyl)benzene

##STR00126##

[0828]2-Chloro-4,5-difluorobenzenesulfonyl chloride (300 mg) was added to
a solution of sodium sulfite (306 mg) and sodium bicarbonate (153 mg) in
water (4 mL). The mixture was heated to 150.degree. C. in a sealed
microwave vial for 400 seconds and allowed to cool. The mixture was
treated with bromoacetic acid (253 mg) in water (1 mL), and heated to
150.degree. C. for 300 seconds then allowed to cool, following which the
precipitate was removed by filtration and dried in vacuo to give the
desired compound (132 mg). The material was used without further
purification.

[0831]Caesium carbonate (523 mg) was added to a solution of
3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3--
yl)benzamide (234 mg) and 1,2,4-trifluoro-5-(methylsulfonyl)benzene (169
mg) in acetonitrile (5 mL) was added. The mixture was heated in a sealed
microwave vial to 160.degree. C. for 7000 seconds and left to cool before
being filtered and washed with acetonitrile (10 mL). The filtrate was
evaporated in vacuo and chromatographed on silica, eluting with 0 to 10%
methanol in ethyl acetate. This Cave incomplete resolution so the mixture
was purified by preparatory HPLC using a gradient of 5 to 95%
acetonitrile in water to afford the desired compound (5.1 mg)

[0833]The preparation of
3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3--
yl)benzamide was described in Example 12.

[0834]The preparation of 1,2,4-trifluoro-5-(methylsulfonyl)benzene is
described below.

1,2,4-Trifluoro-5-(methylsulfonyl)benzene

##STR00128##

[0836]2,4,5-Trifluorophenyl sulfonyl chloride (979 mg) was added to a
solution of sodium sulfite (306 mg) and sodium bicarbonate (153 mg) in
water (4 mL). The mixture was heated to 150.degree. C. in a sealed
microwave vial for 400 seconds and allowed to cool. The mixture was
treated with bromoacetic acid (253 mg) in water (1 mL), and heated to
150.degree. C. for 300 seconds then allowed to cool, following which the
precipitate was removed by filtration and dried in vacuo to give the
desired compound (169 mg). The material was used without further
purification.

[0839]Trimethylsilyl iodide (0.062 mL, 0.434 mmol) was added to a solution
of 3-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(1-
,2,4-oxadiazol-3-yl)phenoxy]benzamide (78 mg, 0.174 mmol) in acetonitrile
(2 mL) and the reaction mixture allowed to stir at RT for 18 hours. The
reaction was diluted with ethyl acetate (15 mL) and quenched by the
addition of saturated aqueous sodium bicarbonate (20 mL). The organic
phase was washed with saturated aqueous thiosulphate solution (20 mL) and
dried (MgSO.sub.4). The volatiles were removed under reduced pressure and
the resulting oil purified by chromatography on silica, eluting with
0-100% ethyl acetate in iso-hexane, to give the title compound as a
colourless solid (64 mg).

[0842]3-{4-[(Hydroxyamino)(imino)methyl]phenoxy}-5-[(1S)-2-methoxy-1-methy-
lethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide was taken up in trimethyl
orthoformate (3 mL) and 2 drops of borontrifluoroetherate added. The
resulting solution was heated to 55.degree. C. in a CEM explorer
microwave for 80 mins. The volatiles were removed under reduced pressure
and the resulting oil chromatographed on silica, eluting with 0-100%
ethyl acetate in iso-hexane, to give the desired compound as a white foam
(295 mg)

[0845]Hydroxylamine (50% w/w solution, 1 mL) was added to a solution of
3-(4-cyanophenoxy)-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-p-
yrazol-3-yl)benzamide (300 mg, 0.74 mmol) in ethanol (3 mL) and the
reaction mixture allowed to stir at RT for 18 hours. The volatiles were
removed in vacuo to give the desired compound as a colourless foam (325
mg).

[0848]To a stirred solution of
3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-%-(1-methyl-1H-pyrazol-3--
yl)benzamide 0.164 mmol) in DMF (1 mL) was added a 1M solution of sodium
hexamethyldisilazide in THF (0.164 mmol). The reaction was stirred at RT
for 10 minutes before adding 4-fluorobenzonitrile (0.164 mmol) The
reaction was stirred overnight at RT, then heated to 60.degree. C. and
stirred for a further 4 hours. The reaction was allowed to cool to RT,
and treated with a further 0.2 equivalents of 4-fluorobenzonitrile and
sodium hexamethyldisilazide, heated to 70.degree. C. and stirred at this
temperature for 3 hours. The reaction was cooled to RT, and treated with
a further 0.2 equivalents of sodium hexamethyldisilazide, warmed to
70.degree. C., and stirred at this temperature overnight. The solvent was
removed in vacuo and the residual oil partitioned between ethyl acetate
and water. The water layer was separated and re-extracted with ethyl
acetate. The combined organic layers were washed with brine, dried
(MgSO.sub.4), filtered and evaporated to a residue which was
chromatographed on silica, using 0-1% methanol in DCM as the eluent, to
give the desired product (60% yield). .sup.1H NMR .delta. (CDCl.sub.3):
1.35 (d, 3H), 3.40 (s, 3H), 3.55 (m, 2H), 3.78 (s, 3H), 4.60 (m, 1H),
6.80 (m, 2H), 7.10 (m, 3H), 7.30 (m, 2H), 7.62 (d, 2H), 8.55 (br s, 1H);
m/z 407 (M+H).sup.+, 405 (M-H).sup.-

[0849]The synthesis of
3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy-]-N-(1-methyl-1H-pyrazol-3-
-yl)benzamide is described in Example 12.

[0854]A solution of ethyl
4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(5-methylpyrazin-2-yl)amino]carb-
onyl}phenoxy)benzoate (0.4 g, 0.88 mmol) in THF (16 mL) was added to a
solution of lithium hydroxide monohydrate (0.19 g. 4.43 mmol) in water (8
mL). The mixture was stirred at RT for 72 hours and the THF removed in
vacuo. The aqueous layer was acidified with 1M hydrochloric acid (10 mL),
and the solid precipitate filtered off, washed with water and dried in
vacuo to give the desired compound (0.22 g). The material was used
without further purification.

[0859]The preparation of
3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)b-
enzamide was described in Example 8.

[0860]Example 20 can also be prepared from
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)sily-
l]oxy}-1-methylethoxy)-N-(5-methylpyrazin-2-yl)benzamide in an analogous
fashion to the preparation of Example 8 from
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dime-
thyl)silyl]oxy}-1-methylethoxy)-N-(5-methylpyrazin-2-yl)benzamide,
described earlier. The desired material was isolated following
crystallization from ethyl acetate and isohexane (mpt 169.degree. C.) and
the spectroscopic data was in agreement with that previously reported.

[0861]3-[4-(Azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl-
)silyl]oxy}-1-methylethoxy)-N-5-methylpyrazin-2-yl)benzamide can be
prepared from
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)sily-
l]oxy}-1-methylethoxy)benzoic acid in an analogous fashion to the
preparation of
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dime-
thyl)silyl]oxy}-1-methylethoxy)-N-(5-methylpyrazin-2-yl)benzamide from
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2{[tert-butyl(dimet-
hyl)silyl]oxy}-1-methylethoxy)benzoic acid, describe din Example 8.

[0867]Potassium carbonate (143 mg, 1.04 mmol) was added to a mixture of
3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(5-methyl-1,3-thiazol-2-yl)-
benzamide (160 mg, 0.52 mmol) and 1-(3,4-difluorobenzoyl)azetidine (102
mg, 0.52 mmol) in acetonitrile (5.0 mL), and the stirred mixture heated
at 160.degree. C. in a `Smith Creator Microwave` for 15 hours. The
mixture was allowed to reach ambient temperature and pressure and reduced
in vacuo. The residual oil was partitioned between ethyl acetate (50 mL)
and water (50 mL). The ethyl acetate layer was separated, washed with
brine, dried (MgSO.sub.4), and evaporated to a residue which was
chromatographed on silica, eluting with a gradient of 0-10% methanol in
ethyl acetate, to give the desired compound (30 mg)

[0872]Triethylamine (0.11 mL, 0.79 mmol) and triethylsilane (4.88 mL, 27.3
mmol) were added to palladium (II) acetate (56 mg, 9 mol %) in DCM (14
mL) under an atmosphere of argon. The reaction was stirred for 15 mins
then 3-(benzyloxy)-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyleth-
oxy)-N-(5-methyl-1,3-thiazol-2-yl)benzamide (1.4 g, 2.73 mmol) in DCM (14
mL) added dropwise and stirred for a further 48 hours. The reaction was
filtered through celite and the filtrate concentrated in vacuo to give a
residue which was chromatographed on silica, eluting with a gradient of
50-100% ethyl acetate in isohexane, to give the desired compound (0.18
g).

[0875]DIPEA (7.5 mL) was added to a suspension of
3-{(phenylmethyl)oxy}-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-
ethoxy)benzoic acid (4.5 g, 0.011 mol). HATU (8.6 g, 0.023 mol) and
2-amino-5-methylthiazole (2.46 g, 0.022 mol) in DMF (70 mL). The
resulting mixture was stirred at ambient temperature for 72 hours. The
DMF was removed in vacuo. Water (100 mL) was added and the mixture
extracted with ethyl acetate (3.times.50 mL). The extracts were combined
and washed with brine (100 mL). The solution was dried (MgSO.sub.4),
filtered, and evaporated in vacuo to give the crude product which was
chromatographed on silica, eluting with a gradient of 50-100% ethyl
acetate in isohexane, to give the desired compound. (1.7 g).

[0879]The benzyl ethers used in the preparation of Examples 21a and 21b
were prepared from
3-{(phenylmethyl)oxy}-5-((1S)-9-{[tert-butyl(dimethyl)silyl]oxy}-1-dimeth-
ylethoxy)benzoic acid using the appropriate amine:

[0881]DIPEA (0.36 mL, 1.95 mmol) was added to a suspension of
4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]-
carbonyl}phenoxy)benzoic acid (200 mg, 0.49 mmol), HATU (390 mg, 1.02
mmol) and piperidine (0.19 mL, 1.95 mmol) in DMF (3 mL) and the mixture
stirred at ambient temperature for 24 hours. The solvent was evaporated.
Water (30 mL) was added and the mixture extracted with ethyl acetate
(3.times.15 mL). The combined organic extracts were washed with brine (30
mL), dried (MgSO.sub.4), and evaporated to a residue which was
chromatographed on silica, eluting with a gradient of 0-20% methanol in
ethyl acetate, to give the desired compound (167 mg).

[0883]The following compounds were synthesised in an analogous fashion
from 4-(3-[(S)-2-hydroxy-1-methylethoxy]-5-t
{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)benzoic acid and the
appropriate amine:

[0886]A solution of ethyl
4-(3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-{[(1-meth-
yl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)benzoate (3.78 g, 6.84 mmol) in
THF (100 mL) was added to a solution of lithium hydroxide monohydrate
(1.44 g, 33 mmol) in water (50 mL). The mixture was stirred at ambient
temperature for 72 hours. 1M Hydrochloric acid was added until pH=2 and
the mixture stirred for a further 1 hour. The THF was removed in vacuo
and the solid precipitate filtered off, washed with water and dried in
vacuo to give the desired compound (3.06 g).

[0896]The following compounds were synthesised in an analogous fashion
from 3-fluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyraz-
ol-3-yl)amino]carbonyl}phenoxy)benzoic acid and the appropriate amine:

[0899]A solution of ethyl
3-fluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3--
yl)amino]carbonyl}phenoxy)benzoate (1.8 g, 3.94 mmol) in THF (60 mL) was
added to a solution of lithium hydroxide monohydrate (0.83 g, 19.7 mmol)
in water (30 mL). The mixture was stirred at RT for 72 hours and the THF
removed in vacuo. The aqueous layer was extracted into ethyl acetate (100
mL) to remove any impurities, then acidified with 1M hydrochloric acid
and extracted into ethyl acetate (2.times.100 mL). The combined extracts
were dried (MgSO.sub.4) and the solvent removed in vacuo to give the
desired compound (1.62 g).

[0904]The preparation of
3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3--
yl)benzamide was described in Example 12.

[0905]2-Methylazetidine required for the preparation of Example 23e was
prepared as described in JOC, 26, 1961 138.

[0906]3-Methoxyazetidine hydrochloride required for the preparation of
Example 23f was prepared as follows:

3-Methoxyazetidine Hydrochloride

##STR00164##

[0908]A solution of tert-butyl 3-methoxyazetidine-1-carboxylate (0.32 g,
1.71 mmol) in 3M hydrogen chloride in ethyl acetate (10 mL) was stirred
at RT for 3 hours. The volatiles were removed in vacuo, ethyl acetate was
added to the residue then decanted off and the residue dried in vacuo to
give the desired compound. (0.16 g)

[0913]3-Isopropoxyazetidine hydrochloride used in the preparation of
Example 23g was prepared from tert-butyl 3-hydroxyazetidine-1-carboxylate
in an analogous fashion to 3-methoxyazetidine hydrochloride:

[0917]The following compound was synthesised in an analogous fashion from
4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(5-methylpyrazin-2-yl)amino]carb-
onyl}phenoxy)benzoic acid and the appropriate amine:

[0920]Cesium carbonate (780 mg, 2.40 mmol) was added to a mixture of
3-hydroxy-5-[(1R)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)b-
enzamide (350 mg, 1.2 mmol) and 1-(3,4-difluorobenzoyl)azetidine (235 mg,
1.2 mmol) in dimethylacetamide (5.0 mL) and the stirred mixture heated at
160.degree. C. in a `Smith Creator Microwave` for 2 hours. The mixture
was allowed to return to ambient temperature and pressure and was
partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl
acetate layer was separated, washed with water (5.times.50 mL) brine (50
mL), dried (MgSO.sub.4) and evaporated to a residue which was
chromatographed on silica, eluting with a gradient of 0-10% methanol in
DCM, and then chromatographed by preparative HPLC on C18 reversed phase
using 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA) as eluant. A
10% impurity remained. This mixture (0.12 g, 0.26 mmol) was dissolved in
DMF (3 mL) and imidazole (0.123 g, 1.79 mmol) and
tert-butyldimethylsilylchloride (77 mg, 0.51 mmol) were added. After
stirring at RT for 24 hours water (30 mL) was added and the material
extracted into diethyl ether (2.times.50 mL). The combined extracts were
washed with brine (50 mL), dried (MgSO.sub.4) and evaporated to a residue
which was chromatographed on silica, eluting with a gradient of 0-10%
methanol in chloroform, and then chromatographed by preparative HPLC on
C18 reversed phase using 5-95% acetonitrile (+0.2% TFA) in water (+0.2%
TFA) as eluant. The chromatography fractions were allowed to stand
overnight and the acetonitrile removed in vacuo. The aqueous residue was
basified with saturated aqueous sodium bicarbonate solution and extracted
into ethyl acetate (2.times.50 mL) and the combined extracts reduced in
vacuo to give the desired compound. (30 mg)

[0924]Iodotrimethylsilane (6.64 mL, 47 mmol) was added to a solution of
3-hydroxy-5-[(1R)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)b-
enzamide (2.86 g, 9.38 mmol) in acetonitrile (120 mL) and the resultant
mixture stirred for 24 hours. Methanol (30 mL) was added and the mixture
stirred for 30 minutes, saturated potassium carbonate (30 mL) and
saturated sodium thiosulphate (30 mL) were then added and the mixture
stirred for 20 mins. The acetonitrile was removed in vacuo and water (50
mL) added. The mixture was adjusted to pH4 with 1M hydrochloric acid,
extracted into ethyl acetate (3.times.100 mL) and the combined extracts
washed with brine (50 mL), dried (MgSO.sub.4) and evaporated to a residue
which was chromatographed on silica, eluting with a gradient of 0-50%
methanol in ethyl acetate, to give the desired compound (1.75 g).

[0927]3-(Benzyloxy)-5-[(1R)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyraz-
ol-3-yl)benzamide (4.23 g, 0.011 mol) was dissolved in ethanol (35 mL) and
THF (35 mL) and the flask evacuated and purged with argon (3 times). 10%
Palladium on carbon (0.42 g) was added and the flask further evacuated
and finally purged with hydrogen gas. The reaction mixture was stirred at
ambient temperature for 20 hours until completion. The reaction mixture
was evacuated and purged with nitrogen (3 times). The catalyst was
filtered off through celite and the filtrate concentrated in vacuo to
give the desired compound (2.86)

[0930]DMF (2 drops) was added to a solution of
3-(benzyloxy)-5-[(1R)-2-methoxy-1-methylethoxy]benzoic acid (3.79 g,
0.012 mol) and oxalyl chloride (1.25 mL, 0.015 mol) in DCM (60 mL) and
stirred for 3 hours, following which the organics were removed in vacuo.
The crude material was dissolved in DCM (30 mL) and slowly added, at
0.degree. C., to a stirred suspension of 1-methyl-1H-pyrazol-3-amine
(1.22 g, 0.013 mol) and triethylamine (3.5 mL, 0.025 mol) in DCM (30 mL).
The mixture was stirred at ambient temperature for 24 hours and the
organics evaporated in vacuo. The residue was dissolved in ethyl acetate
(100 mL), washed with 1M aqueous hydrochloric acid (50 mL) and brine (50
mL), dried (MgSO.sub.4), filtered and evaporated in vacuo to give the
crude product which was chromatographed on silica, eluting with a 50%
ethyl acetate in isohexane, to give the desired compound. (4.23 g).

[0936]DIAD (4.6 g, 0.029 mol) was added dropwise to a solution of methyl
3-hydroxy-5-{[phenylmethyl]oxy}benzoate (6 g, 0.023 mol),
(S)-(+)-1-methoxy-2-propanol (2.59 g, 0.029 mol) and triphenylphosphine
(7.53 g, 0.029 mol) in THF (100 mL), under argon, at 0.degree. C. The
reaction was stirred at 0.degree. C. for 1 hour and at RT for 20 hours.
The volatiles were removed in vacuo and isohexane/ethyl acetate 2:1 added
followed by stirring for 1 hour. A white solid was removed by filtration
and the filtrate was evaporated to a residue which was chromatographed on
silica, eluting with a gradient of 0-20% ethyl acetate in isohexane, to
give the desired compound (5.11 g).

[0940]3-[4-(Azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-[(1R)-2-hydroxy-1-me-
thylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.23 g, 0.48 mmol (60%
pure)) and triethylamine (0.2 mL, 1.44 mmol) were dissolved in ethanol (8
mL) and the flask evacuated and purged with argon (3 times). 10%
Palladium on carbon (23 mg) was added and the flask further evacuated and
finally purged with hydrogen gas. The reaction mixture was stirred at
ambient temperature for 6 days until completion. The reaction mixture was
evacuated and purged with nitrogen (3 times). The catalyst was filtered
off through celite and the filtrate concentrated in vacuo to a residue
which was chromatographed on silica, eluting with a gradient of 0-10%
methanol in ethyl acetate. An impurity remained at a level of 40%. This
mixture (0.27 g, 0.6 mmol) was dissolved in DMF (5 mL) and imidazole
(0.29 g, 4.2 mmol) and tert-butyldimethylsilylchlorde (180 mg, 1.2 mmol)
were added. After stirring at RT for 20 hours water (30 mL) was added and
the mixture extracted into diethyl ether (2.times.50 mL). The combined
extracts were washed with brine (50 mL) dried (MgSO.sub.4) and evaporated
to a residue which was chromatographed on silica, eluting with a gradient
of 0-10% methanol in ethyl acetate, and then chromatographed by
preparative HPLC on C18 reversed phase using 5-95% acetonitrile (+0.2%
TFA) in water (+0.2% TFA) as eluant. The chromatography fractions were
allowed to stand overnight and the acetonitrile removed in vacuo. The
aqueous residue was basified with saturated aqueous sodium bicarbonate
solution and extracted into ethyl acetate (2.times.50 mL) and the
combined extracts reduced in vacuo to give the desired compound. (78
mg)<

[0944]Cesium carbonate (1.12 g, 3.44 mmol) was added to a mixture of
3-hydroxy-5-[(1R)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)b-
enzamide (500 mg, 1.72 mmol) and 1-(3-chloro-4-fluorobenzoyl)azetidine
(367 mg, 1.72 mmol) in dimethylacetamide (5.0 mL) and the stirred mixture
heated at 160.degree. C. in a `Smith Creator Microwave` for 2 hours. The
mixture was allowed to return to ambient temperature and pressure and was
partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl
acetate layer was separated, washed with water (5.times.50 mL) brine (50
mL), dried (MgSO.sub.4) and evaporated to a residue which was
chromatographed on silica, eluting with a gradient of 0-10% methanol in
ethyl acetate, and then chromatographed by preparative HPLC on CIS
reversed phase using 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA)
as eluant. An impurity remained at the 40% level and this material was
used crude in the next step (0.21 g).

[0945]m/z 485, 487 (M+H).sup.+

[0946]The preparation of
3-hydroxy-5-[(1R)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)b-
enzamide was described in Example 25.

[0948]10% Hydrochloric acid (2 mL) was added to a solution of
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dime-
thyl)silyl]oxy}-1-methylethoxy)-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamid-
e (950 mg, 1.58 mmol) in methanol (20 mL). The reaction was stirred at
ambient temperature for 1 hour, saturated sodium bicarbonate solution
added and the methanol evaporated. The aqueous residue was taken to pH2
and extracted with ethyl acetate. The extracts were combined, washed with
brine, dried (MgSO.sub.4), filtered and evaporated in vacuo to give the
crude product which was chromatographed on silica, eluting with ethyl
acetate, to give the desired compound (400 mg) which was recystallised
from ethyl acetate (mpt 173.degree. C.-175.degree. C.).

[0956]10% Hydrochloric acid (2 mL) was added to a solution of
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-[{tert-butyl(dimethyl)sily-
l]oxy}-1-methylethoxy)-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide (580
mg, 1.0 mmol) in methanol (20 mL). The reaction was stirred at ambient
temperature for 1 hour, saturated sodium bicarbonate solution added and
the methanol evaporated. The aqueous residue was taken to pH2 and
extracted with ethyl acetate. The extracts were combined, washed with
brine, dried (MgSO.sub.4), filtered, and evaporated in vacuo to give the
crude product (275 mg) which was recystallised from ethyl acetate (m pt
159.degree. C.-160.degree. C.).

[0966]The preparation of
3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N--
(1-methyl-1H-pyrazol-3-yl)benzamide was described in Example 5.

[0967]The preparation of 1-[(4-fluorophenyl)sulfonyl]azetidine is
described below:

1-[(4-Fluorophenyl)sulfonyl]azetidine

##STR00183##

[0969]Azetidine (0.25 g, 4.35 mmol) was added to a solution of sodium
hexamethyldisilylazide (0.85 g, 4.6 mmol) in THF (10 mL) at 0.degree. C.
and reaction mixture stirred for 10 minutes. 4-fluorobenzenesulfonyl
chloride (0.85 g, 4.35 mmol) was subsequently added and the reaction
mixture was allowed to warm up to ambient temperature overnight. The
reaction mixture was concentrated in vacuo and the residue taken up in
ethyl acetate and water. The organic layer was separated and then dried
(MgSO.sub.4), filtered and evaporated to give a waxy, yellow solid (75
mg).

[0974]The synthesis of 1-(3,4-difluorobenzoyl)azetidine is described in
Example 8, the synthesis of tert-butyl
3-[(3-hydroxy-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoyl)a-
mino]-1H-pyrazole-1-carboxylate is described below:

[0976]A solution of tert-butyl
3-[(3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzo-
yl)amino]-1H-pyrazole-1-carboxylate (90 mg, 0.144 mmol) in 1:1 mixture of
THF/ethanol was evacuated and purged with nitrogen (.times.3). 10%
Palladium on carbon was added and the reaction mixture was evacuated and
purged with nitrogen and then evacuated and finally purged with hydrogen
gas. The reaction mixture was left to stir at ambient temperature under
an atmosphere of hydrogen for 6 hours. The Palladium catalyst was
filtered through diatomaceous earth. The filtrate was evaporated to give
a crude solid (70 mg) m/z 534 (M+H).sup.+, 532 (M-H).sup.-

[0981]Lithium hydroxide monohydrate (12.14 g, 0.289 mol) in water (100 mL)
was added to a solution of methyl
3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoate
(62 g, 0.131 mol) in THF (300 mL) and warmed to 43.degree. C. The
reaction was stirred for 16 hours, the THF removed in vacuo and the
resultant mixture acidified to pH 5 with 10% w/v citric acid. This was
extracted with ethyl acetate (2.times.300 mL) and the combined organic
layers were dried MgSO.sub.4), filtered and evaporated to afford the
title compound (60.2 g).

[0984](2R)-1-[(Triisopropylsilyl)oxy]propan-2-ol (56.1 g, 242 mmol) was
added to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (50
g, 194 mmol) and triphenylphosphine (63.5 g, 242 mmol) in dry THF (500
mL), at to 0.degree. C., followed by addition of DIAD (47.6 mL, 242 mmol)
over 45 minutes under an argon atmosphere. The reaction was stirred at
0.degree. C. for 1 hour and allowed to warm up to RT over an hour then
stirred at RT for 1 hour. The THF was evaporated and a mixture of ethyl
acetate (80 mL) and hexane (120 mL) was added. This mixture stirred for 2
hours and filtered. The precipitate was washed with a mixture of ethyl
acetate (20 mL) and hexane (180 mL) and the filtrate evaporated. The
residue was purified by column chromatography, eluting with 1:20 to 1:10
ethyl acetate:hexanes, to afford the title compound (65.5 g).

[0991]A suspension of 1-(cyclobutylsulfonyl)-4-fluorobenzene (100 mg, 0.47
mmol), cesium carbonate (162 mg, 0.5 mmol) and
3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-{(1S)-1-methyl-2-[(triisopropyls-
ilyl)oxy]ethoxy}benzamide (210 mg, 0.47 mmol) in dimethylacetamide (10 mL)
was heated at 115.degree. C. for approximately 6 hours. Water was added
to the reaction mixture and extracted with ethyl acetate (3.times.40 mL).
The organic phase was washed with water (3.times.30 mL), saturated brine
solution and dried (MgSO.sub.4). This was evaporated and the residue
chromatographed on silica, eluting with 50-100% ethyl acetate in hexanes,
to give clear oil, which foamed up under high vacuum (65 mg).

[1002]10% Palladium on carbon was added to
3-(benzyloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-{(1S)-1-methyl-2-[(triisopro-
pylsilyl)oxy]ethoxy}benzamide (21.7 g, 40.4 mmol) in dry THF (480 mL)
under argon. The reaction mixture was degassed and placed under a
hydrogen balloon and stirred for 16 hours. The atmosphere was replaced
with argon and mixture was filtered through diatomaceous earth then the
filtrate evaporated and dried under high vacuum for 1 hour to give the
title compound (18.2 g).

[1007]The preparation of
3-(benzyloxy)-5-(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy benzoic
acid was described in Example 30.

[1008]The following compound was prepared in an analogous fashion to
Example 31, from
3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-{(1S)-1-methyl-2-[(triisopropyls-
ilyl)oxy]ethoxy}benzamide and 1-(cyclopropylsulfonyl)-4-fluorobenzene

[1011]Trimethylsilyl iodide (0.080 mL, 0.559 mmol) was added to a solution
of 3-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(1-
H-pyrazol-3-yl)phenoxy]benzamide (50 mg, 0.112 mmol) in acetonitrile (2
mL) and the reaction mixture allowed to stir at RT for 18 hours. The
reaction was diluted with ethyl acetate (15 mL) and quenched by the
addition of saturated aqueous sodium bicarbonate solution (20 mL). The
organic phase was washed with saturated aqueous thiosulphate solution (20
mL) and dried (MgSO.sub.4). The volatiles were removed under reduced
pressure and the resulting oil purified by chromatography on silica,
eluting with 0-100% ethyl acetate in iso-hexane, to give the title
compound as a colourless solid (40 mg).

[1025]A suspension of
3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N--
(1-methyl-1H-pyrazol-3-yl)benzamide (200 mg, 0.477 mmol), potassium
carbonate (136 mg, 0.95 mmol) and
2-chloro-4,5-difluoro-N,N-dimethylbenzamide (106 mg, 0.45 mmol) in
acetonitrile (3.5 mL) was heated in a microwave reactor at 160.degree. C.
for 2 hours. The reaction mixture was quenched with water and extracted
with DCM (2.times.6 mL). The organic layer was dried (MgSO.sub.4),
filtered and concentrated in vacuo. The residue was then chromatographed
by preparatory reverse phase HPLC using a gradient of 5-95% acetonitrile
in water (containing 0.2% TFA) on a Phenomenex Luna 10u C18 (2) 100 A
(150.times.21.2 mm) column to give the title compound (37 mg).

[1027]The preparation of
3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N--
(1-methyl-1H-pyrazol-3-yl)benzamide was described in Example 5.

[1028]The preparation of 2-chloro-4,5-difluoro-N,N-dimethylbenzamide is
described below:

2-Chloro-4,5-difluoro-N,N-dimethylbenzamide

##STR00203##

[1030]A solution of 2-chloro-4,5-difluorobenzoic acid (385 mg, 2.0 mmol)
in DCM (5 mL) was treated with
(1-chloro-2-methylprop-1-en-1-yl)dimethylamine (293 mg, 2.2 mmol) and
stirred under argon for 1 hour. The mixture was then treated with
triethylamine (0.56 mL, 4.0 mmol) and a 2M solution of dimethylamine in
THF (1.2 mL. 0.4 mmol), and stirred for 18 hours. The mixture was diluted
with DCM (5 mL) and 2M hydrochloric acid (4 mL) and separated. The
organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo
to afford the title compound (425 mg). The residue was used without
further purification.

[1032]The following compound was prepared from
3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N--
(1-methyl-1H-pyrazol-3-yl)benzamide and
2,4,5-trifluoro-N,N-dimethylbenzamide in an analogous fashion to that of
Example 33.

[1035]A solution of 2,4,5-trifluorobenzoic acid (123 mg, 0.7 mmol) in DCM
(1.7 mL) was treated with (1-chloro-2-methylprop-1-en-1-yl)dimethylamine
(103 mg, 0.77 mmol) and stirred under argon for 1 hour. The mixture was
then treated with triethylamine (0.29 mL, 2.1 mmol) and azetidine
hydrochloride (78 mg, 0.84 mmol), before being left to stir for 18 hours.
The mixture was diluted with DCM (5 mL) and 2M hydrochloric acid (4 mL)
and Separated. The organic layer was dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue was treated with suspension of
3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1-pyrazol-3-y-
l)benzamide (200 mg, 0.477 mmol) and potassium carbonate (284 mg, 2.05
mmol) in acetonitrile (3.5 mL) was heated in a microwave reactor at
160.degree. C. for 1.5 hours. The reaction mixture was filtered and
concentrated in vacuo. The residue was then chromatographed on silica,
eluting with 0-15% methanol in ethylacetate, to give the title compound
(74 mg).

[1040]10% Hydrochloric acid (2 mL) was added to a solution of
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dime-
thyl)silyl]oxy}-1-methylethoxy)-N-1,3-thiazol-2-ylbenzamide (585 mg, 1.0
mmol) in methanol (20 mL). The reaction was stirred at RT for 1 hour,
saturated sodium bicarbonate solution added and the methanol evaporated.
The aqueous residue was taken to pH 2 and extracted with ethyl acetate.
The extracts were combined, washed with brine, dried (MgSO.sub.4),
filtered and evaporated in vacuo to give the crude product which was
chromatographed on silica, eluting with 1% methanol in ethyl acetate, to
give the desired compound (283 mg).

[1048]10% Hydrochloric acid (1 mL) was added to a solution of
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)sily-
l]oxy}-1-methylethoxy)-N-1,3-thiazol-2-ylbenzamide (284 mg, 0.5 mmol) in
methanol (10 mL). The reaction was stirred at RT for 1 hour, saturated
sodium bicarbonate solution added and the methanol evaporated. The
aqueous residue was taken to pH 2 and extracted with ethyl acetate. The
extracts were combined, washed with brine, dried (MgSO.sub.4), filtered,
and evaporated in vacuo to give the crude product which was
chromatographed on silica, eluting with 1% methanol in ethyl acetate, to
give the desired compound (113 mg).

[1056]A mixture of
3-[4-(azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tert-butyl(dime-
thyl)silyl]oxy}-1-methylethoxy)-N-pyrazin-2-ylbenzamide (37 mg, 0.062
mmol) in methanol (0.5 mL) and 3.5M hydrochloric acid (0.018 mL) was
stirred for 30 mins at RT. The solution was taken to pH 6 with saturated
aqueous sodium bicarbonate solution and the volatiles were removed in
vacuo. The residue was taken into ethyl acetate (10 mL) and washed with
water (2 mL), brine (2 mL), dried (MgSO.sub.4), filtered and the solvents
removed in vacuo to give the crude product which was chromatographed on
silica, eluting with 0-10% methanol in ethyl acetate, to give the desired
compound as a white foam (21 mg).

[1061]1-Chloro-N,N,2-trimethyl-1-propenylamine (0.073 mL, 0.55 mmol) was
added to a solution of
3-[4-(azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tert-butyl(dime-
thyl)silyl]oxy}-1-methylethoxy)benzoic acid (260 mg, 0.5 mmol) in DCM (10
mL) and stirred at RT for 1 hour. 2-Amino-5-methylpyrazine (95 mg, 1
mmol) and pyridine (0.081 mL, 1.0 mmol) were added and the reaction
stirred for a further 30 mins. The solvent was removed in vacuo. Water
(10 mL) was added and the mixture extracted with ethyl acetate
(2.times.10 mL). The extracts were combined and washed with 1N citric
acid, water (10 mL) and brine (10 mL), dried (MgSO.sub.4), filtered, and
evaporated in vacuo to give the crude product which was chromatographed
on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane,
to give the desired compound (37 mg).

[1062]m/z 597 (M+H).sup.+

[1063]3-[4-(Azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl-
)silyl]oxy}-1-methylethoxy)-N-pyrazin-2-ylbenzamide was prepared in an
analogous fashion from
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)sily-
l]oxy}-1-methylethoxy)benzoic acid:

TABLE-US-00030
Structure m/z NMR
##STR00216## 563 (M - H).sup.-

[1064]The preparation of
3-[4-(azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tert-butyl(dime-
thyl)silyl]oxy}-1-methylethoxy)benzoic acid is described in Example 8a.

[1065]The preparation of
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)sily-
l]oxy}-1-methylethoxy)benzoic acid is described in Example 20.

[1067]3-[4-(Azetidin-1-ylcarbonyl)-2-chloro-3-fluorophenoxy]-5-[(1S)-2-hyd-
roxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (162 mg; 0.322
mmol) was dissolved in methanol (10 mL). Triethylamine (97 mg, 0.967
mmol) was added and the flask evacuated and purged with nitrogen (3
times). 10% Palladium on carbon (25 mg) was added and the flask further
evacuated and finally purged with hydrogen gas. The reaction mixture was
stirred at ambient temperature for 7 days until completion. The reaction
mixture was evacuated and purged with nitro-en (3 times). The catalyst
was filtered off, the filtrate concentrated in vacuo and purified by
preparatory reverse phase HPLC using a gradient of 5-95% acetonitrile in
water (containing 0.2% TFA) on a Phenomenex Luna 10u C18 (2) 100 A column
to give the title compound (60 mg).

[1073]The preparation of
3-fluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3--
yl)amino]carbonyl}phenoxy)benzoic acid was described in Example 23.

[1074]The preparation of 2-azabicyclo[2.1.1]hexane hydrochloride salt is
described below:

2-Azabicyclo[2.1.1]hexane Hydrochloride Salt

##STR00219##

[1076]A mixture of ethyl 2-azabicyclo[2.1.1]hexane-2-carboxylate (0.35 g,
2.25 mmol) and concentrated hydrochloric acid (10 mL) was refluxed for 4
hours, cooled and the volatiles removed in vacuo. Toluene was added then
removed in vacuo and the resultant product dried under reduced pressure
to give the desired compound which was used without further purification
(0.24 g).

[1077]Ethyl 2-azabicyclo[2.1.1]hexane-2-carboxylate was prepared in
accordance with literature precedence (J. Org. chem. 1998, 63, 8558) and
the spectroscopic data was in agreement with literature values.

[1079]3.5M Hydrochloric acid (1.0 mL) was added to a solution of
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)sily-
l]oxy}-1-methylethoxy)-N-(1,5-dimethyl-1H-pyrazol-3-yl)benzamide (232 mg,
0.4 mmol) in methanol (10 mL). The reaction mixture was stirred for 45
minutes then saturated sodium bicarbonate added until the pH was adjusted
to 7. The mixture was reduced in vacuo. The residue was dissolved in
ethyl acetate (50 mL), washed water (25 mL) and brine (25 mL). Dried
(MgSO.sub.4) and reduced to a white foam. The crude product was purified
by chromatography on silica, eluting with 0-10% methanol in ethyl
acetate, to obtain the required product as a white foam (123 mg).

[1081]The following example was prepared in an analogous fashion from
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((S)-2-{[tert-butyl(dimet-
hyl)silyl]oxy}-1-methylethoxy)-N-(1,5-dimethyl-1H-pyrazol-3-yl)benzamide

[1083]DIPEA (517 mg, 3.00 mmol) was added to a solution of
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)sily-
l]oxy}-1-methylethoxy)benzoic acid (364 mg, 0.75 mmol),
3-amino-1,5-dimethylpyrazole (100 mg, 0.90 mmol) and HATU (599 mg, 1.58
mmol) in DMF (3.0 mL) and the mixture stirred for 24 hours, Water (25 mL)
was added and the mixture extracted with ethyl acetate (2.times.95 mL)
dried (MgSO.sub.4) and reduced to a brown oil. The crude product was
purified by chromatography on silica, eluting with ethyl acetate, to give
the required product as a clear oil. (232 mg).

[1084]m/z 480 (M+H).sup.+

[1085]3-[4-(Azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl-
(dimethyl)silyl]oxy}-1-methylethoxy)-N-(1,5-dimethyl-1H-pyrazol-3-yl)benza-
mide used in the preparation of Example 40a was prepared in an analogous
fashion from
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dime-
thyl)silyl]oxy}-1-methylethoxy)benzoic acid.

TABLE-US-00032
Structure m/z NMR
##STR00223## 497 (M + H).sup.+

[1086]The preparation of
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)sily-
l]oxy}-1-methylethoxy)benzoic acid was described in Example 20.

[1087]The preparation of
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dime-
thyl)silyl]oxy}-1-methylethoxy)benzoic acid was described in Example 8.

[1088]3-Amino-1,5-dimethylpyrazole is a compound whose preparation is
described in the literature (J. Het. Chem. 1982, 19(6), 1267).

Biological

Tests:

[1089]The biological effects of the compounds of formula (I) may be tested
in the following way:

(1) Enzymatic Activity

[1090]Enzymatic activity of recombinant human pancreatic GLK may be
measured by incubating GLK, ATP and glucose. The rate of product
formation may be determined by coupling the assay to a G-6-P
dehydrogenase, NADP/NADPH system and measuring the linear increase with
time of optical density at 340 nm (Matschinsky et al 1993). Activation of
GLK by compounds can be assessed using this assay in the presence or
absence of GLKRP as described in Brocklehurst et al (Diabetes 2004, 53,
535-541).

[1093]E. Coli transformations were generally carried out by
electroporation. 400 mL cultures of strains DH5a or BL21(DE3) were grown
in L-broth to an OD 600 of 0.5 and harvested by centrifugation at 2,000
g. The cells were washed twice in ice-cold deionised water, resuspended
in 1 mL 10% glycerol and stored in aliquots at -70.degree. C. Ligation
mixes were desalted using Millipore V Series.TM. membranes (0.0025 mm)
pore size). 40 mL of cells were incubated with 1 mL of ligation mix or
plasmid DNA on ice for 10 minutes in 0.2 cm electroporation cuvettes, and
then pulsed using a Gene Pulser.TM. apparatus (BioRad) at 0.5
kVcm.sup.-1, 250 mF. Transformants were selected on L-agar supplemented
with tetracyline at 10 mg/mL or ampicillin at 100 mg/mL.

Expression

[1094]GLK was expressed from the vector pTB375NBSE in E. coli BL21 cells,
producing a recombinant protein containing a 6-His tag immediately
adjacent to the N-terminal methionine. Alternatively, another suitable
vector is pET21(+)DNA, Novagen, Cat number 697703. The 6-His tag was used
to allow purification of the recombinant protein on a column packed with
nickel-nitrilotriacetic acid agarose purchased from Qiagen (cat no
30250).

[1095]GLKRP was expressed from the vector pFLAG CTC (IB1 Kodak) in E. coli
BL21 cells, producing a recombinant protein containing a C-terminal FLAG
tag. The protein was purified initially by DEAE Sepharose ion exchange
followed by utilisation of the FLAG tag for final purification on an M2
anti-FLAG immunoaffinity column purchased from Sigma-Aldrich (cat no.
A1205).

(2) Oral Glucose Tolerance Test (OGTT)

[1096]Oral glucose tolerance tests were done on conscious Zucker obese
fa/fa rats (age 12-13 weeks or older) fed a high fat diet (45% kcal fat)
for at least two weeks prior to experimentation. The animals were fasted
for 2 hours before use for experiments. A test compound or a vehicle was
given orally 120 minutes before oral administration of a glucose solution
at a dose of 2 g/kg body weight. Blood glucose levels were measured using
a Accucheck glucometer from tail bled samples taken at different time
points before and after administration of glucose (time course of 60
minutes). A time curve of the blood glucose levels was generated and the
area-under-the-curve (AUC) for 120 minutes was calculated (the time of
glucose administration being time zero). Percent reduction in glucose
excursion was determined using the AUC in the vehicle-control group as
zero percent reduction.

##STR00224##

[1097]Compounds of the invention generally activate glucokinase with an
EC.sub.50 of less than about 500 nM. For example, Example 3a has an
EC.sub.50 of 50 nM.